AU683620B2 - Substituted pyrimidines for control of diabetic complications - Google Patents

Description

OPI DATE 26/04/94 AOJP DATE 14/07/94 APPLN. ID 46697/93 111li 111 111 I 11111li PCT NUMBER PCT/US93/06446111 ii1111111 i I111i N AU9346697 I NTEtI~I,z4tt viL t^rrLI. ijiviN ru aLi anL.L t~jvi*4Lt%~ its L an LimLIx tv Ll*'dI IW1%1 I A %A Ij (51) International Patent Classiication 5 (11) International Publication Number: WO 94/07867 C07D 239/42, 417/14 Al (3 neainlPbiainDt; 1 pi 94(40.4 A61 K31/505(4)ltrtlnlPbctinDt:4Api194(409) (21) International Application Number: PCT/US93/06446 (72) Inventors; and (75) Inventors/Applicants (for iS only): MYLARI, Banavara, L.

(22) International Filing Date: 12 July 1993 (12,07.93) [US/US]; 6 Quinlcy Way, Waterford, CT 06385 (US).

OATES, Peter, J. [US/US]; 16 Ferry View Drive, Galcs Ferry, CT 06335 SIEGEL, Todd, W. [US/US]; 27 Priority data: Lochbourne Drive, Clinton, CT 06413 ZEM.

07/952,222 28 September 1992 (28.09.92) US BROWVSK1, William, J. [US/US]; 1315 Route 163, Oakdale, CT 06370 (US).

Parent Application or Grant (74) Agents: RICHARDSON, Peter, C. et al.; Pizer Inc., Pa- (63) Related by Continuation tent Department, 235 East 42nd Street, New York, NY us 07/952,222 (CIP) 100 17 (US).

Filed on 28 September 1992 (28,09.92) (81) Designated States: AU, CA, JP, KR, NO, NZ, US, Euro- (71) Applicant (for all designated States except US). PFIZER pean patent (AT, BE, CH, DE, DK, ES, FR, GB, OR, INC. [US/US]; 235 East 42nd Street, New York, NY IE, IT, LU, MC, NL, PT, SE).

100 17 (US).

Published 111th in:ternational search report.

83j;20 (54) Title: SUBSTITUTED PYRIMIDINES FOR CONTROL OF DIABETIC COMPLICATIONS R 2 N R 3

R

N R N, R 4 (57) Abstract This invention relates to methods of inhibiting sorbitol dehydrogenase, lowering fructose levels, and treating or preventing diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy or diabetic macroangiopathy in a mammal using pyrimidine derivatives of formula wherein R 1

R

2

R

3

R

4 and R 5 are defined as below, and to pharmaceutical compositions containing such derivatives. It also relates to certain novel substituted pyrimidines having the above formula. It also relates to mutual prodrugs of compounds of above formula and aldose reductase inhibiting compounds, and to pharmaceutical compositions comprising a compound of above formula and an aldose reductase inhibitor.

I

WO 94/07867 PCT/US93/06446 -1- SUBSTITUTED PYRIMIDINES FOR CONTROL OF DIABETIC COMPLICATIONS Background of the Invention The present invention relates to novel pyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase, lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions containing such pyrimidine derivatives and related compounds.

S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitcl, a precursor of fructose, from glucose via the enzyme aldose reductase.

We have found that pyrimidine derivatives of the formula I, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.

Summary of the Invention The present invention also relates to the use of substituted pyrimidines of the formula I, as defined below, to treat or prevent diabetic complications in mammals, and to pharmaceutical compositions containing such pyrimidines.

Compounds of the formula I are those having the formula 1 WO 94/07867 WO 9407867PCr/US93/06446 -2-

R

2

R

3 N R N R wherein RI is hydrogen, OF 3 (C,-C,)alkyI, (Cl-C 6 )alkyl-S-(C,-C,)alkyl, (C 1 -C,)alkyl-SO- (C,-C,)alkyl, (Cj-C,)alkyl-S0 2

-(C

1 -C,)alkyl, hydroxy-(C,-C,)alkyl, dihydroxy-(Cl-C,)alkyl, (Cl-C,)alkoxy, (C,-C 6 )alkoxycarbonyl-(C,-C 6 )alkyl, aryl selected from phenyl and naphthyl, aryl-(C,-C,)alkyl wherein the aryl moiety is selected from phenyl and riaphthyl,

(C

1 -C,)alkoxycarbonylaryl wherein the aryl moiety is selected from phenyl and naphthyl, aryl-(Cl-C,)alkyl wherein the aryl moiety is selected from phenyl and naphthyl, aryl-(C 1 C,)alkyloxy Wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, and benzothienyl;, heteroaryl-(C 1 C,)alkyl wherein heteroaryl is defined as above, or heteroaryl-(C,-C, 6 )alkyloxy wherein heteroaryl is defined as above, and wherein said aryl and heteroaryl groups, the aryl moieties of said aryl-(C,-C.)alkyl, (Cl-C,)alkoxycarbonylaryl and aryl-(C 1

-C,

6 )alkyloxy and the heteroaryl moiety of said heteroaryl-(Cl-C,)alkyl may optionally be substituted with one or more substituents independently selected from chioro, bromo, (C 1

-C

6 )alkyl, (C 1 CWalkoxy, -S-(C,-C,)alkyl, -SO-(Cl-C,)alkyl, -S0 2 -(Cl-C,)alkyl, hydroxy-(C 1 -0 6 )alkyl and trifluoromethyl; or RI is a group of the formula Wz wherein the dotted line represents an optional double bond, W, Q and Z are independently selected from hydrogen, (Cl-C 6 ,)alkyl and trifluoromethyl, phenyl, fury[, triazolyl, thiazolyl and thienyl, wherein said phenyl, furyl, triazolyl, thiazolyl and thienyl may optionally be substituted with one or more -substituents independently selected from (Cl-C,)alkyl, (C,-C,)alkoxy, trifluoromethyl and hydroxy; WO 94/07867 WO 947867PT/US93/06446 -3- 0 11 or R' is a group of the formula -C-118, wherein R" Is hydrogen, (C,-C,)alkyl, aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl and benzothienyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chioro, bromo, nitro, trifluoromethyl, (C,-C,)alkoxy, -S-(C,-C,)alkyl, -SO-(C,-C,)alkyl and -S0 2 -(Cl-C, 6 )alkyl; or RI is a group of the formula 1*

Y-Q-CH-R

7 1, wherein R' is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, tria2,lyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothienyl and quinolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from chloro, bromo, (C,-C,)alkyl, (C,-C,)alkoxy, -S-(C 1 -C,)alkyl, -SO-(C 1 -Ce)alkyl, -S0 2

-(C

1 -C,)alkyl and trifluoromethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, aryl selected from phenyl and naphthyl, heteroaryl selected from furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, bromo, nitro, trifluoromethyl, (Ci- C.)alkyl, (C,-C,)alkoxy, -S-(C,-C,)alkyl, -SO-(C,-C,)alkyl and -S0 2 -(Cl-C,)alkyl; R 2 and R' are independently selected from hydrogen, (Cl-C,)alkyl, phenyl and phenyl-(C 1

-C

4 )alkyl, wherein said phenyl and the j'henyl moiety of said phenyl -(Cl-

C

4 )alkyl may optionally be substituted with one or more substituent-; independently selected from (C,-C,)alkyl, (Cl-C,)alkoxy, chloro, bromo and trifluoromethyl; or R 2 and R' form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted with from zero to two substituents, independently selected from (C,-C,,)alkyl, -CONH 2

-SO

2

NH

2

C

4 )alkylsulfamoyl, N,N-di-(C 1

-C

4 )alkylsulfamoyl, 6 )alkoxycarbonyl, N, N-di-(Cl-

C

4 )alkylcarbamoyl, N-(C 1

-C

4 )alkylcarbamoyl, N-phenylcarbamoyl, 6 )alkylcarbonyl, phenylcarbonyl, (C,-C,)alkylsulfonyl, (C 1 -C,)alkylsUlfinyl, phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein the heteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonyl are selected from furyl, thienyl, thiazolyl, and WO 94/07867 PCT/US93/06446 -4oxazolyl, and wherein the phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl, phenylcarbonyl and phenylsulfonyl may optionally be substituted with one or more substituents independently selected from (Cl-C 4 )alkyl, (C,-C 4 )alkoxy, chloro, bromo, nitro, amino, cyano and trifluoromethyl;

R

4 is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C,-C,)alkyl,

(C

1 -C,)hyd. xyalkyl, (Cl-C,)alkoxy, plienyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted with one or more substituents independently selected from ;iioro, bromo, trifluoromethyl, (C,-C,)alkyl, (C 1 -C,)alkoxy,-

S-(C,-C

6 )alkyl, -SO-(Ci-C,)alkyl, -S0 2 -(C,-C,)alkyl and hydroxy; and

R

5 is hydrogen, (Ci-C,)alkyl, (C,-C,)alkoxy, trifluoromethyl, (C,-Ce)hydroxyalKyl, -S-(Cl-C,)alkyl, -SO-(C,-Ce)alkyl, -S0 2 -(C,-C,)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionally be substituted with one or more substituents independently selected from chloro, bromo, trifluoromethyl, (C,-C 6 )alkyl, (C,-C,)alkoxy, C,)alkyl, -S0 2 6 )alkyl and hydroxy.

Several of the substituted pyrimidines of formula I, as well as processes for preparing them, are referred to in European Patent Application 470,616A2, published February 12, 1992 and European Patent Application 384,370A1, published August 29, 1990. These references are incorporated herein by reference in their entirety.

More specifically, this invention relates to a pharmaceutical composition comprising a sorbitol dehydrogenase inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

This invention also relates to a method of inhibiting the enzyme sorbitol dehydrogenase in a mammal, including a human, comprising administering to said mammal a sorbitol dehydrogenase inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising an namount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, and a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, ~c WO 94/07867 WO 9407867PCIVUS93/0'., 6 comprising administering to said mammal a fructose lowering effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof.

This Invention also relates to a pharmaceutical composition comprising an amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof, 6 effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy In a mammal, Including a human, and a pharmaceutically acceptable carrier.

This Invention also relates to a method of treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy In a mammal, Including a, human, comprising administering to said mammal an amount of a compound of iv.e formula 1, or a pharmaceutically acceptable salt thereof, effective In treating or preventing such complication.

This Invention also relates to those compounds of the formula I wherein RI Is C,)aikyl, (C,.C,)alkyi.S0 2 (C-"O'Alkyl, dlhydroxy-(CI-CO)alkyl, arl, heteroaryl, heteroaryl, -CO)alkyl, Mrl.(C,-C,)alkyi, .C,)aIkoxycarbonyIaryl, arl.(C,-C,)alkyloxy or heteroaryl.(C,.C)akyloxy, wherein said aryl and the aryl moieties of said

C

0 )aikyl, (C,-CO)alkoxycarbanylaryI, and arl.(C,.C,)alkyioxy are Independently selecte! from phenyl and naphthyl, and wherein said heteroaryl and the heteroarl moieties i~ said hotercaryl-(Ci-CO)alkyl and ho~eroaryI.(C,.C,)alkyIlo-'y are Independently selected from wherein the ary moiety Is selected from phenyl and naphthylt heteroaryl selected from pyridyl, luryl, tetrahydrofuryl, thienyl, imldazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyi, and wherein said aryl and heterot 4 )iy and the aryl and heteroaryl moieties of said heteroary.(C,-C.)alkyl, aryi'.(Ct.C 6 )alkyl, (Cl- C,)aikoxycarbonylary, aryl.(Ci.C 6 )alkyloxyand heteroary..(CI-CO) aikyloxymay optionally be substituted with one or more substituents, preferably with one or two substituents, Independently selected from chioro, bromo, (C,-C,)alkyl, (C,.C 0 )aIkoxy, SO..(C,-Ca)aikyi, -S0 2 -A(C,)akyI, hydroxy-(C 1 -C,)alkyi and trifluoromethyl: or RI is a group of the formula WO 94/07867 WO 9407867PCr/US93/06446 .6- 6 wherein the dotted line represents an optional double bond, W, Q and Z are Independently selected from hydrogen, (CI-C 8 )alkyl and trifluoromethyl, phenyl, furyl, triazolyl, thiazolyl and thionyl, wherein said phenyl, furyl, triazolyl, thiazolyl and thienyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from (CI-CO)alkyl, (CI-C,)alkoxy, triluoromethyl and hydroxy; 0 or RI Is a group of the formulat -C-85, wherein RI Is hydrogen, (C 1 '.C,)alkyl, aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, trlazolyl, thlazo'yl, oxazolyl, benzothiazolyi, benzofuranyl and benzothlenyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from chloro, bromo, nitro, tritluoromethyl, (C 1 .C,)alkoxy, Ca)alkyl, -SO.(C 1 -0 8 )alkyl and -S0 2 -(Ci-C,,)alkyl, or RI Is a group of the formula Y-0 CH R, wherein R 7 Is aryl selected from phenyl nd naphthyi, or heteroaryl selected from pyridyl, furyl, thienyl, imldtkzolyl, pyrazolyl, trlxzolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothlenyl and quinolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from chioro, bromo, (C 1

-C

0 )alkyl, (C,-C 0 )alkoxy, -S-(C 1

.C

8 )aikyl, .SO.(C 1 -C,)alkyl, -S0 2 -(C,-C,)aikyl and trifluoromethyl, and Y Is hydrogen, benzyl, acetyl, benzoyi, aryl selected from phenyl and naphthyl, heteroaryl selected from furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substltuents, pref erably with from zero tc' two substituents, Independently selected from chloro, bromo, nitro, triluoromethyl, .C,)alkyl, .C,)alkoxy, -S-(C 1 -C,)alkyI, .SO.(C 1 C.)aikyl and -S0 2 -(C,-Ce)alkyl.

WOQ 94/07867 PCT/US93/06446 .7- These novel compounds are hereinafter referred to, collectively, as compounds of the formu!.v IA. This Invention also relates to the pharmaceutically acceptable acid addition and base salts of the novel compounds of formula IA.

This Invention also relates to mutual prodrugs of a compound of the formula I and an aldorie reductase Inhibiting compound.

This Invention also relates to compounds of the formula R2 N"

R

R

R 5 C H R 4 0 0 11 11 wherein R 2 5

ISY

3 C0- or Q 2

NH

2

CQ

2

S-R

2 -HNC and R 2 1 is aryl selected from phenyl and naphthyl, wherein said aryl may optionaily be substituted with one or more substituents, preferably with one or two substituents, independently selected from chloro, bromo, (C,.C 8 )alkyl, (C,-C,)alkoxy, 8 )alkyl, .SO-(C,-C,)alkyl, -S0 2 .(Cl-

C

0 ,)alkyl, hydroxy-(C 1 .C,)alkyl and trifluoromethyl;

R

2 and RI are Independently selected from hydrogen, (C,-C,)alkyi, phenyl and phenyl-(C 1

-C

4 )alkyi, wherein said phenyl and the phenyl moiety of said phenyl

C

4 )aikyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from (C,-C,)alkyl, (C 1

-C

8 )alkoxy, chloro, bromo and trifluoromethyl; orR 2 and R 3 form, together with the nitrogen to which they are attached, a cyclic group selected from azetldino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted with from zero to two substituents Independently selected from (C,-C,)alkyl, -CONH 2

-S

2 2 N-(Cj-

C

4 )aikylsulfamoyl, N, N-dI-(C,-C 4 )alkylsulfamoyl, (C,-C,)akoxycarbonyl, N, N-di-(C 1

C

4 )alkylcarbamoyl, N-(C 1

-C

4 ).alkylcarbamoyl, N-phenylcarbamoyl, (C.

CO)alkylcarbonyl, phenylcarbonyl, (C 1 -C,)alkylsulfony 1 (C,-C,\alkylsulfinyl, phenylsulfonyl, heteroarylsufonyl and heteroarylcarbonyl, wherein the heteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonyl are selected from furyl, WO 94/07867 WO 9407867PCI'/US93/06446 -8thienyl, thiazolyl and oxazolyl, and wherein the phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl, phenylcarbonyl and phenylsulfonyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from (C 1

-C

4 )alkyl, (0 1

-C

4 )alkoxy, chloro, bromo, nitro, amino, cyano and trifluoromethyl;

R

4 is hydrogen, chioro, bromo, cyano, nitro, trifluoromethyl, amino, (C,-C,)alkyl, (0 1 -C,)hydroxyalkyl, (C 1

-C

6 ,)alkoxy, phenyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from chloro, bromo, trifluoromethyl, (C,-C,)alkyl, (C,-C 8 ,)alkoxy, -S-(C,-C,)alkyl, -SO-(C 1 -C,)alkyl, -S0 2 -(C,-C,)alkyl and hydroxy; RI Is hydrogen, (C,-C,)alkyl, (Cl-C,)alkoxy, trifluo rom ethyl, (C 1

-C

6 )hydroxyalkyl, -S-(C,-C,)alkyl, .SO-(C,.C,)alkyl, -S0 2 -(C,-C,)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from chloro, bromo, C,)alkyl and hydroxy; RI Is hydrogen or R7 R 7 is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothlenyl and qulnolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably with from zero to two substituents, Independently selected from chloro, bromo, (C 1 -C,)alkyl, (C,-C 8 ,)alkoxy, 8 )alkyl, *SO.(C,-C 0 )alkyl, -S0 2 -(C,-C,)alkyl and trifluoromethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, aryl selected from phenyl and naphthyl, or heteroaryl selected fr-om furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from chloro, bromo, nitro, trifluoromethyl, (C 1 -C,)alkyl, (C,-C,)alkoxy, 6 )alkyl, 6 )alkyl and -S0 2 (Cl-C,)alkyl;

I

WO 94/07867 PCr/US93/06446 o y 4 o0 Y' Is or Y 2 is absent the carbon to which R' is attached 0 11 is directly bonded to Y" is hydrogen or (Cl-C,)alkyi; and

Y

3 Is selected from the follow,-ng groups: WO 94/07867 PCT/US93/06446 R 1 2 0 1 R N: S

R

1 N 0

N

0 x II R '4

R

1 5 P -R X II I WO 94/07867 WO 947867Pr/US93/06446 and

R

12

B

wherein A is CH 2

CH

2

CH

2

CH(CH

3 or CH 2

-C.-NH;

B is oxygen or sulfur; R' is selected from phenyl, benzothiazol-2-yI, benzoxazol-2-yi, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl-1 ,2,4-oxadiazoland 5-phenyl-1 ,2,4-oxadlazol-3-yl, and RI may optionally be substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, methyl, methylthio, methoxy, hydroxy and trifluoromethyl; RIO and RII are independently selected from hydrogen, fluorine, chlorine, bromine, (Cl-C 4 )alkyl, (C,-C 4 )alkylthio, (C 1

-C

4 )alkoxy and trifl uorom ethyl; or RIO and R" together, with the carbons to which they are attached, form a group of the formula RE G or (CH )P wherein p is 1 cr 2; D and E are independently selected from -OH 2 oxygen and sulfur, except that D and E cannot both be oxygen and cannot both be sulfur; RI I and R" 3 are independently selected from hydrogen, fluorine, chlorine, bromine, (0 1

-C

4 )alkyl, (Ci-

C

4 )alkylthlo, (C 1

-C

4 )alkoxy and trifluoromethyl;, and F and G are independently selected from -OH- and nitrogen;

R

12 and R' 3 are independently selected from hydrogen, fluorine, chlorine, bromine, (C 1 -0 4 )alkyl, (C 1

.C

4 )alkylthio, (C 1 -C4)alkoxy and trifluoromethyl; WO 94/07867 PCT/US93/06446 -12- K is oxygen, sulfur, SO or SO,;

R

1 4 is hydrogen, fluoro, chloro, bromo, methyl, nitro, cyano, methanesulfonyl or benzoyl; is hydrogen, fluoro, chloro, bromo, carboxy, (C,-C 3 )alkyl, (C,-C 3 )alkoxy or benzyloxy; is hydrogen, fluoro, chloro, bromo or (C,-C 3 )alkyl; or R 1 and R 1 together with the carbon atoms to which they are attached, form a 7,8-benzo ring;

R'

7 is (C,-C 4 )alkyl, trifluoromethyl or (CH 2 wherein n is 0, 1 or 2 and Ar is phenyl optionally substituted with one or two substituents independently selected from methoxy, fluoro, chloro and bromo: is hydrogen, methyl or ethyl; or R' 7 and R' 8 together with the carbon to which they are attached, form a saturated 4 or 5 membered carbocyclic spiro ring; and

R"

9 is hydrogen or methyl; with the proviso that: when K is other than oxygen, R 1 4 is fluoro, chloro, cyano or nitro, and R" 6 and R' 6 do not form a 7,8-benzo ring; and when K other than oxygen or R' 7 is other than methyl, ethyl or trifluoromethyl, both R' 8 and R' 9 are hydrogen; and when Y 3 is a group of the formula XIVA, R 9 is benzothiazol-2-yl or substituted benzothiazol-2-yl; and the pharmaceutically acceptable salts of such compounds.

0

II

Compounds of the formula Y'-C-OH wherein Y 3 is one of the above groups VII to XIV are known aldose reductase inhibitors. Compounds of the formula VI wherein 0

R

2 5 is Y 3

-C-O-Y

2 are conjugates and mutual prodrugs of such aldose reductase inhibitors and the pharmaceutically active compounds of the formula I wherein R' is CHO2H, -CHR 7 OH or hydroxy-(C,-C,)alkyl. As mutual prodrugs, they are expected to release in vivo both pharmaceutically active agents a compound of the formula I wherein R' is -CH 2 OH, -CHR'OH or hydroxy-(C,-C 6 )alkyl and an aldose reductase WO 94/07867 PCT/US93/06446 -13- 0 inhibitor of the formula Y'-C-OH.

Compounds of the formula O0N-CH 2 -SO,-R 2

-NH

2 wherein R 2 is defined as above, are also known aldose reductase inhibitors. Compounds of the formula VI 0 O

II

wherein R 2 5 is O 2

NH

2

CO

2

S-R

26 -HN-C- are conjugates and mutual prodrugs of such aldose reductase inhibitors and the pharmaceutically active compounds of the formula I wherein R 1 is -CH 2 OH, -CHR0OH or hydroxy-(C,-C,)alkyl. As mutual prodrugs, they are expected to release in vivo both pharmaceutically active agents a compound of the formula I wherein R' is -CH 2 OH, -CHR 7 OH or hydroxy-(C,-C 6 )alkyl and an aldose reductase inhibitor of the formula 0 2

N-CH

2

-SO,-R

2

G-NH

2 Preferred embodiments of this invention include those compounds of the 0 O

I!

formula VI, and pharmaceutically acceptable salts thereof, wherein R 25 is Y 3 C-0-Y 2

Y

2 is not absent and: Y 3 is a group of the formula VII, R 9 is phenyl, substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, A is -CH 2 and R'o and R" are either both methyl or they form, together with the carbons to which they are attached, a group of the formula I OR

Y

3 is a group of the formula VIII, R 9 is phenyl, substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, A is -CH 2 and R' 2 and R' 3 are independently selected from bromo and chloro; Y 3 is a group of the formula IX and each of R' 2 and R' 3 is hydrogen; (d)

Y

3 is a group of the formula X and R' 2 and R 13 are independently selected from Ce)alkoxy and trifiuoromethyl; Y 3 is a group of the formula XI and R 12 and R' 3 are independently selected from (C,-C,)alkyl; Y 3 is a group of the formula XII, R 9 is phenyl, substituted phenyl or benzothiazol-2-yl, A is -CH 2 and and R' 3 are independently selected from chloro and bromo; or Y 3 is a group of the formula XIII, WO 94/07867 WO 94/07867PCr/US93/06446 -14each of R11 and R' 9 is hydrogen, each of R 17 and R" 8 Is methyl, R" 5 is 6-chloro or 6fluoro and R' 6 Is 7-chioro or 7-fluoro.

Preferred embodiments of this invention also include those compounds of the formula VI that are mutual prodrugs of a compound of the formula I and an aldose 0 11 reductase inhibitor of the formula Y-C-QH-, wherein such aldose reductase inhibitor is selected from: 3,4-d Ih yd ro-4-oxo-3- [[(5-trif Iu oro methyl) -2-b enzoth azolyl] -m ethyl] -1 phthalazineacetic acid; 3,A-dihydro-4-oxo-3-[[(5,7-difluoro)-2-benzothkzolyl]-methyl]-1 -phthalazineacetic acid; 3,4-dihydro-4-oxo-3-[[(5,7-dichloro)-2-benzothiazolyl]-methyl-1 -phthalazineacetic acid; 2-[4-(4,5,7-trif luorobenzoth iazo 1-2-yl)rmneth yl-3,4-d ih yd ro-3-oxo-2H- 1 '4benzothiazin-2-y] acetic acid; 5-d m ethyl -6-oxo-1 -(5-trifluoromethyl-benzothiazolylmethyl)-1 1 6-dihydropyridazin-3-yl]-acetic acid; [4,5-dimethyl-6-oxo-1 -(5,7-difluoro-benzothiazolyl methyl)-1 1 6-di hyd ro-pyri dazin-3yl]-acetic acid; [4,5-dimethyl-6-oxo-1 -(5,7-dichlorobenzothiazol-2-ylmethyl)-1 .6-dihydro-pyridazin- 3-yII-acetic acid; 4-oxo-3 [((5-trif Iu oromethyl)-benzothiazol-2-ylm ethyl] 3,4,5,6,7,8-hexahydrophthalazin-1-yl]-acetic acid; 4-oxo-3-([(5,7-difluoro)-benzothiazol-2-ylmethyl]-3,4,5,6,7 1 8-hexahydro-phthalazin- 1 -yl]-acetic acid; 4-oxo-3-[[(5,7-dichloro)-benzothiazol-2-ylmethyl]-3,4,5,6,7,8-hexahydrophthalazin-1 -yl] -acetic acid; N-[[5-trifluoromethyl)-6-n iethoxy-1 -naphthalenyl]thiioxomethyl]-N-methylglycine; 3,4-dihydro-4-oxo-3-(4-bromo-2-fluorobenzyl)-1 -phthalazineacetic acid; (Z)-3-(carboxymethyl-t(2E)-methylphenylpropenylidenel-rhodanine, 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1 ,2,3,4-tetrahydro-2,4-dioxo-1 quinazolinyl] -acetic acid; WO 94/07867 PCr/US93/06446 2R,4R-6,7-dichloro-4-hydroxy-2-methylchromar- acetic acid; 2R,4R-7-chloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid; and 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazlne-4-acetic acid.

This invention also relates to a pharmaceutical composition comprising: an amount of a mutual prodrug of a compound of the formula I and an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt of such a prodrug, effective in lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes; and a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level nf fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, comprising administering to said mamml a fructose lowering effective amount of a mutual prodrug of a compound of the Tormula I and an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt of such a prodrug.

This invention also relates to a pharmaceutical composition comprising: an amount of a mutual prodrug of a compound of the formula I and an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt of such a prodrug, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal, including a human; and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or prevnnting a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal, including a human, comprising administering to said mammal an amount of a mutual prodrug of a compound of the formula I and an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt of such a pi drug, effective in treating or preventing such complication.

This invention relates to a pharmaceutical composition comprising an amount of a compound of the formula VI, or a pharmaceutically acceptable salt thereof, effective in lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, and a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the'level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes,

I

WO 94/07867 PCT/US93/06446 -16comprising administo-ing to said mammal a fructose lowering effective amount of a compound of the formula VI, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising an amount of a compound of the formula VI, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neurop .thy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal, including a human, and a pharmaceutically acceptable carrier.

This invention also relat.. to a method of treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula VI, or a. pharmaceutically acceptable salt thereof, effective in treating or preventing such complicatici,.

Compounds of the formulae XV-XIX, which are defined below, and their pharmaceutically acceptable salts, are also known compounds that exhibit activity as aldose reductase inhibitors. These compounds have the following structures: WO 94/07867 WO 9407867PCT/US93/06446 -17- NH

NH

R

21 HN 0R 2 1 H N 0 21 XV XVI R 20

OH

0 F F 0 0 n0 CH 3 10 CH 3 XVI I XV I I and IS02eC H 2 N2

XIX

0 11 wherein L is oxygen, CH 2 sulfur or J is hydrogen, methyl or -CNN 2 G is CH or N; R 20 and R 2 1 are independently selected from hydrogen, fluorine, chlorine, (C 1 C,)alkyl, (C,-C,)alkoxy, -S-(C 1

-C

6 )alkyl, -SO-(C,-C,)alkyl or -SG 2 -(Cl-C,)alkyl; M ;s phenyl, naphthyl or a heteroaryl group selected from furan, morpholine, pyrrOlidine, tetrahydroisoquinoline, thiophene, thiazole, oxazole, berzofuran, WO 94/07867 WO 9407867PCI'/US93/06446 benzothiophiene, benzothiazole, benzoxazole and indole, wherein said phenyl, naphthyl and heteroaryl groups may optionally be substituted with up to three substituents independently selecteJ from chioro, fluoro, brorno, cyano, nitro, hydroxy, carboxy, amino (C 1 -C,)alkylamino, dial kylamino, (C 1 -C,)alkc.ioylamino, (C1 -C 6 ,)alkanoyl, (C,-C,)alkyl, (C 2 -C,)alkenyl, (C 3 -C6)alkenyloxy, fluoro-(C 1

-C

6 )alkyl, (C 1 -Cr)alkoxy, fluoro-

(C

1

-C

4 )alkoxy, (Cl-C,)hydroxyalkyl, carbamoyl, (C 1

-C

7 )alkylcarbamoyl, (C 1

C

7 )dialkylcarbamoyl, sulfamoyl, (C 1 .)alkysulfamoyl, (C,-C,)dialkylsulfamoyl, (Ci-

C

6 )alkoxycarbonyl,(Cl.C4)alkylenedioxy,(C-C)alkanesuifonamido,-S(C-C)aky,-SO- (Cl-C,)alkyl, -S0 2 -(C1-C,,)alkyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido, and benzenesulfonamido, and wherein said phenyl and the pheny; moieties of said phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido may optionally be substituted with a substituent selected from chlorine, fluorine, (C 1

C

4 )alkyl (C 1

-C

4 )alkoxy and 0

R

22 HI I

-Y

5 H 1 2

R

2 wht Y' is oxygen or sulfur, or Y' s absent the phenyl ring is boncied to the carbon to which R 22 and R 2 are attached), and R 2 and R 2 are independently selected from hydrogen and (C 1

-C

4 )alkyl, and the phenyl moiety lo which the -NHCOC(R 22 (R 23 sidechain is attached may optionally be substituted with from one to three substituents independently selected from hydrogen, halo, trifluoromethyl, nitro, cyano,

(C-C

4 )alkyl, (C 1

-C

4 )alkoxy and (C 1

-C

4 )alkanoyl, or any adjacent pair of substituents may form, together with the carbons to Which they are attached, a benzo ring which may optionalli be substituted with a substituent independently selected from halo, (C 1

C

4 )alkyl and (C 1

-C

4 )alkoxy; 0 11 with the proviso that: when J is -C NH 2 G is CH and L is oxygen; and M is not 2-carboxypheiyl.

This invention also relates to a pharmaceutical composition comprising: an amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof,

I

WO 94/07867 PCT/US93/06446 .19that is effective in lowering the level of fructose in one or more of the tissues of a mammal, Including a human, that are affected by diabetics; an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal, Including a human, that are affected by diabetes and a pharmaceutically acceptable carrier.

This Invertion also relates to a method of lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, comprising administering to said mammal a fructose lowering effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with a fructose lowering effective amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising: an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microanglopathy or macroanglopathy in a mammal, including a human; an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy or diabetic microanglopathy or macroanglopathy in a mammal, including a human; and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microanglopathy or macroanglopathy in a mammal, Including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication, in combination with an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication.

This invention also relates to a pharmaceutical composition comprising: an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetico; an amount of a

I

WO 94/07867 PCT/US93/06446 compound of the formula XV, XVI, XVII, XVIII or XIX, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal, Including a human, that are affected by diabetes and a pharmaceutically acceptable carrier.

6 This invention also relates to a method of lowering the level of fructose in one or more of the tissues of a mammal, including a human, that are affected by diabetes, comprising administering to said mammal a fructose lowering effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with a fructose lowering effective amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising: an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microanglopathy or 16 macroanglopathy in a mammal, including a human; &n amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy or diabetic microanglopathy or macroanglopathy in a mammal, including a human; and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic rephropathy, or diabetic mlcroangiop&lhy or macroanglopathy in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication, in combination with an amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication.

Preferred embodiments of this invention include those pharmaceutical compositions and methods set forth above, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, that is employed is a compound wherein R' is (C,-C)hydroxyalkyl, (C,-Ce)alkoxy, imidazolyl, furyl, pyrazolyl, tetrahydrofuryl, thienyl WO 94/07867 PCT/US93/06446 -21or triazolyl, or R' is Y-O-CH-R 7 wherein R 7 is benzothlazolyl, furyl, imidazolyl, pyrazolyl, thienyl, triazolyl, (C,-C 0 )alkyl or trifluoromethyl, and Y is hydrogen or (Ci-C,)alkyl, and

R

2 and R 3 form, together with the nitrogen to which they are attached, a group of the formula -N N-X

\R

24 wherein X is carbon or -SO- and R 2 4 is amino, (C,-C,)alkylamino, di-(C,-C)alkylamino or pyridyl.

Particularly preferred embodiments of this invention are those pharmaceutical compositions and methods referred to above, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, that is employed a compound wherein R' is (Cl-C,)alkyl, xyalkyl, (C,-C,)alkoxy, furyl, triazolyl, or tetrahydrofuryl, or R' is Y-O-CH-R 7 wherein R' is benzothiazolyl, furyl, thiazolyl, thienyl or trifluoromethyl, and Y is hydrogen or (C,-C,)alkyl, each of R 4 and R 5 is hydrogen, and R 2 and R 3 together with the nitrogen to which they are attached, form a group of the formula R27 N-SO -NR7 R28 wherein R 27 and R 2 8 are, independently, methyl or ethyl.

Other particularly preferred embodiments of this invention are those pharmaceutical compositions and methods referred to above, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, that is employed is a compound wherein R' is (C,-C,)hydroxyalkyl, furyl or triazolyl, or R' is Y-O-CH-R 7 wherein R 7 is furyl, thienyl or trifluoromethyl and Y is hydrogen, each of R 4 and R 5 is hydrogen, and R 2 and R 3 together with the nitrogen to which they are attached, form a group of the formula WO 94/07867 WO 9407867PCr/US93/06446 -22-

*-R

2 8 wherein R 27 and R" 6 are, Independently, hydrogen, methyl or ethyl.

Preferred embodiments of this invention also include the pharmaceutical compositions and methods set forth above, wherein the compound of formula 1, or pharmaceutically acceptable salt thereof, that is employed Is selected from: 4-[4-(N-methylsulfamoyl)-piperazino]-2-methylpyrimidine; 4-(4-(N-sulfamoyi)-piperazino]-2-methylpyrimidine; N-dimethylsulfamoyi)-piperazino]-2-methylpyrimidine; 4-[4-(N-methylsuifamoyl)-piperizino]-2-hydroxymethylpyrimidine; 4-[4-(N-sulfamoyl)-piperlzino]-2-hydroxymethylpyrimidine; and 4-[4-(N,N-dimethylsulfamoyl)-piperizino]-2-hydroxymeii wlpyrimidine.

Preferred embodiments of this invention also Include those pharmaceutical compositions and methods set forth above that comprise or employ a composition comprising an aidose reductase Inhibitor selected from: (4-amino-2,6-dimethylphylsulfonyl)nitromethane; N, N-diisopropyl-N'-(3,5-dimethyl-4-(nitromethylsulf onyi)phenyl] oxamide; N-[3,5-dimethyl-4-(nitromethyisulfonyl)phenyi]-2-(piperidino)giyoxamide; (2,6-dimethyi.4-(phenylacetamido) phenyisuif onyl] nitrom ethane; [2,6-dimethyl-4-(2-phenoxyacetamido)phenylsulfony] nitromethane; (2,6-dimethyl-4-(2-(3.methylphenoxyacetamido)phenyl)sulfonyl] nitromethane;, (2,6.dimethyi-4-(2-(3-chiorophenoxyacetamido)phenyl)sufony] nitromethane; [2,6-dimethy-1 -((2,4,6-trimethyiphenyi)acetamido)phenysulfonyl] nitromethane;, 2,6-dimethyi-4-((2-methylphenyi)acetamido)phenyisufonyI nitromethane; 2,6-dimethyi-4-((2-fiuorophenyi)acetamido)phenyisufonyI nitromethane; 2-(nitromethylsulfonyl)thiophene; N-(nitromethyisulfonyi)morpholine; N-(nitromethylsulfonyl)piperidine; N-(nitromethyisuifonyi)indoline; d-6-fluoro-spiro(chroman-4,,4-imidazolidine)-2',5'-dione;

I

WO 94/07867 PCT/US93/06446 -23- 2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione; 2,7-difluoro-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione; 2,7-difluoro-5-methoxy-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione; ,2-b]pyridine-5,3'-pyrrolidine)2,5'-dicne; d-cis-6'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,4'-4'H-pyrano(2,3spiro[imidazolidine-4,5'(6H)-quinoline]2,5-dione-3'-chloro-7',8'-dihydro-7'-methyl-, and (2S,4S)-6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-carboxamide.

"A sorbitol dehydrogenase inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof,' as used herein, refers to an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that exhibits sorbitol dehydrogenase inhibiting activity, or an amount of such compound or salt that yields a metabolite in vivo that exhibits sorbitol dehydrogenase inhibiting activity.

The term 'alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.

The term 'alkoxy', as used herein, includes O-alkyl groups wherein "alkyl" is defined as above.

The term "one or more substituents," as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.

The acids that may be used to prepare pharmaceutically acceptable acid addition salts of those compounds of formulae I and VI that are basic in nature are those which form non-toxic acid addition salts, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzene-sulfonate, p-toluenesulfonateand pamoate 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formulae I and VI that are acidic in nature are those that form non-toxic WO 94/07867 PCT/US93/06446 -24base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations potassium and sodium) and alkaline earth metal cations calcium and magnesium), ammonium or water-soluble amine addition salts such as Nmethylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

Description of the Drawings Figure 1 illustrates the dose dependent lowering of erythrocyte fructose by 4-[4- (N,N-dimethylsulfamoyl)oiperizino]-2-methylpyrimidine (referred to in Figurs 1 as "Compound in diabetic rats.

Figure 2 Illustrates the dose dependent elevation of erythrocyte sorbitol by 4-[4- (N,N-dimethylsulfamoyl)piperizino]-2-methylpyrimidine (referred to In Figure 2 as "Compound in diabetic rats.

Figure 3 illustrates the dose dependent lowering of nerve fructose by dimethylsulfamoyl)piperizino]-2-methylpyrimidine (referred to in Figure 3 as 'Compound in diabetic rats.

Figure 4 illustrates the dose dependent elevation of nerve sorbitol by dimethylsulfamoyl)piperizino]-2-methylpyrimidine (referred to in Figure 4 as "Compound in diabetic rats.

Figure 5 illustrates the dose dependent in vitro inhibition of sorbitol dehydrogenase by sera from rats dosed with 4-[4-(N,N-dimethylsulfamoyl)piperizino]-2methylpyrimidine (referred to in Figure 5 as "Compound Figure 6 illustrates the dose dependent in vitro inhibition of sorbitol dehydrogenase by urine from rats dosed with 4-[4-(N,N-dimethylsulfamoyl)piperizino]-2methylpyrimidine (referred to in Figure 6 as "Compound Detailed Description of the Invention Many of the substituted pyrimidines of the formula I are known compounds.

These may be prepared from commercially available or known starting materials by the procedures set forth in European Patent Application 470616A2, published February 12, 1992 and European Patent Application 384,370A1, published August 29, 1990.

Compounds of the formula XV may be prepared as described in United States Patent 4,130,714, which issued to Reinhard Sarges on December 19, 1978, United States Patent 5,066,659 which issued to Christopher A. Upinski on November 19, 1991,

I

WO 94/07867 PCT/US93/06446 United States Patent 4,566,670, which issued to Christopher A. Upinski on December 3, 1985, United States Patent 4,980,357, which issued to Goldstein et al. on December 1990, United States Patent 4,540,704, which issued to Ueda et al. on September 1985, and United States Patent 4,985,573, which issued to Kurono et al. on January 15, 1991. Compounds of the formula XVI may be prepared as described in United States Patents 4,436,745 and 4,438,272, which issued to Billie M. York, Jr. on March 13, 1984 and March 20, 1984, respectively. All of the foregoing documents are incorporated herein by reference in their entirety.

Compounds of the formulae VII and VIII may be prepared as described in United States Patent 5,039,672, which issued to Eggler t al. on August 13, 1991. Compounds of the formula XIX may be prepared as described in European Patent Applications EP 304190, EP 408713, EP 409449, EP 469887 and EP 469888, which were published, respectively, on February 22, 1989, January 23, 1991, January 30, 1991, February 1992 and February 5,1992, United States Patent 5,110,808, which issued to Brittain et al. on May 5, 1992, United States Patent 5,102,905, which issued to Brown et al. on April 7, 1992, and United States Patent 5,096,918, which issued to Keith B. Mallior on March 17, 1992. All of the foregoing documents are incorporated herein by reference in their entirety.

0 Compounds of the formula Y 3 -C-OH, wherein Y 3 Is a group of the formula VII, as defined above, may be prepared as described in United States Patent 4,251,528, which issued to Brittain et al. on February 17, 1981, United States Patent 4,996,204, which issued to Mylari et al. on February 26, 1991, United States Patent 4,939,140, which issued to Larsen et al. on July 3, 1990, PCT Patent Application PCT/US 92/01603, which was filed on March 9, 1992, European Patent Application EP 436307, which was published on July 10, 1991, and French Patent Application FR 2647676A1, which was 0

II

published on December 7, 1990. Compounds of the formula Y 3 -C-OH, wherein Y 3 is a group of the formula IX, as defined above, may be prepared as described in United States Patent 4,464,382, United States Patent 4,791,126 and United States Patent 4,831,045, which issued to Tanouchi et al. on, respectively, August 7, 1984, December WO 94/07867 PCT/US93/06446 -26- 13, 1988 and May 16, 1989. All of the foregoing documents are incorporated herein by reference in their entirety.

0

II

Compounds of the formula Y-C-OH wherein Y 3 is a group of the formula X, as defined above, may be prepared as described in United States Patent 4,391,825, which issued to Bellini et al. on July 5, 1983, and in United States Patent 4,568,693, United S'iates Patent 724 and United States Patent 4,705,882, which issued to Sestanj et al. on, February 4, 1986, July 15, 1986 and November 10, 1987.

0

II

Compounds of the formula Y'-C-OH wherein Y 3 is a group of the formula XI, as defined above, may be prepared as described in United States Patent 4,771,050, which issued 0

II

to Meguro et al. on September 13, 1988. Compounds of the formula Y 3 -C-OH wherein

Y

3 is a group of the formula XII, as defined above, may be prepared as described by Billon et al, Eur. J. Med. Chem., 25, 121 (1990). All of the foregoing documents are incorporated herein by reference in their entirety.

0 O

II

Compounds of the formula Y 3 -C-OH wherein Y 3 is a group of the formula XIII, as defined above, may be prepared as described in United States Patent 4,883,410, which issued to Christopher A. Upinski on August 1, 1989. Compounds of the formula 0

II

Y

3 -C-OH wherein Y 3 is a group of the formula XIV, as defined above, may be prepared as described in European Patent Application 325375, which was published on July 26,

O

II

1989. Compounds of the formula Y-C-OH wherein Y 3 is a group of the formula XIVA, as defined above, may be prepared as described in European Patent Application 492667A1, which was published on July 1, 1992. All of the foregoing documents are incorporated herein by reference in their entirety.

WO 94/07867 PCT/US93/06446 -27- Methods of preparing the various compounds and compositions of this invention are described below. Unless otherwise noted, in the reaction schemes and discussion that follow, R' through PR 8 Q, W, Y, Y 2

Y

3

Y

4 5 A, B, D, E, G, J, L, and M are defined as above.

Reaction schemes 1-3 below illustrate methods of preparing the novel compounds of the formula IA.

WO 94/07867 WO 9407867PCr/US9.3/06446 -28- SCHEME 1

R

2 R 3 N N HOHl 2 C N R R 2 R 3

N

HC

z

N.

P

7 HC N

PR

4 P R 3 p

R

6 HC N4

OH

p N C" 0 1Y WO 94/07867 WO 9407867PCI'/US93/06446 -29- SCHEME 2 R 2 pl N1-1R 3 R 2 R 3 N R N N R 3

RP

N 4 N N GZ H CH C

N

WO 94/07867 WO 947867Prl US 93/06446 SCHEME 3

NH

R. NH 2 cl R R 4

R

2 'IeR 3 (R1 optionally substituted ar-yl, optionally substituted heteroaryl dihydroxy-(Cl-C 6 )alky] (Cl-C 6 )alky]-S-(Cl-C 6 )al kyl 1), aryl-(C 1 -C6)alkyloxy wherein the aryl moiety is optionally substituted, aryl-(C 1

-C

6 )alkyl wherein the aryl moiety is optionally substituted, or heteroaryl-(C 1

-C

6 )al kyl wherein the heteroaryl moiety is optionally substituted) WO 94/07867 PCT/US93/06446 -31- 0

II

Referring to schem e 1, compounds of the formula IA wherein R' is -CR 6 and R' is hydrogen may be prepared by oxidizing the corresponding compounds wherein R' is hydroxymethyl (-CH20H). Oxidizing agents that may be used include chromic acid, silver oxide and activated manganese dioxide, with activated manganese dioxide being preferred. When chromic acid is used, the preferred solvent is water or an aqueous

(C

3 -C,)alkyl ketone acetone) and the reaction temperature, which can range from about -780C to about 250C, is preferably from about -100C to about 0OC. When silver oxide or activated manganese dioxide is used, the solvent is preferably a halocarbon solvent such as chloroform or methylene chloride, and the reaction temperature, which can range from about 0OC to about 1000C, is preferably between about 200C and the reflux temperature of the solvent.

0

II

Compounds of the formula IA wherein R' is -CR 6 and R' is other than hydrogen may be prepared by first reacting the corresponding compound wherein R' is formyl (CHO) with an organolithium reagent of the formula R 6 U or an appropriate Grignard reagent of the formula R'MgX wherein X is chloro, bromo or iodo, and then oxidizing the reaction product. The initial reaction with the Grignard or organoli aium reagent is generally conducted in a hydrocarbon solvent such as n-pernane, n-hexane or nheptane, at a temperature from about -70 oC to about 0 C, preferably from about -700 C to about-20 0 C. The subsequent oxidation step may be carried out as described above for the oxidation of compounds wherein R' is hydroxymethyl.

Vr\" Compounds of the formula IA wherein R' is YOCHR 7 and Y is hydrogen may be 0

II

prepared by reacting the corresponding compounds wherein R' is -CH with an organolithium reagent of the formula RUL or an appropriate Grignard reagent of the formula R 7 MgX, in the manner described above for preparing compounds of the formula 0 I wherein R' is -CR 6 and R 6 is other than hydrogen. Treatment of the resulting WO 94/07867 PCT/US93/06446 compounds with an appropriate reagent of the formula Y-L, wherein Y is other t1- -n hydrogen and L is a 'eaving group, in the presence of a strong base yields t' corresponding compounds wherein R 1 is YOCHR 7 and Y is other than hydrogen.

Examples of bases that may be used are sodium hydride in dimethylform:mide and a (C,-C)alkyllithium in a hydrocarbon solvent n-pentane or n-hexane). SuitaHle leaving groups include chloro, bromo, iodo and OS02-(C,-C,)-alkyl. The reaction temperature can range from about -2000 to about 100 C, and is preferably from about 0 °C to about 60 0

C.

Scheme 2 illustrates the preparation of compounds of the formula IA wherein R' is a group of the formula Referring to scheme 2, such compounds may be prepared by reacting the 0

II

corresponding compounds wherein R' is -C-W with a Wittig reagent of the formula

Q

(CH,)

3 P=C-Z. Typically, this reaction is carried out in a nonprotic solvent such as dimothylformamide or a (C 4 -C,)alkylether, preferably tetrahydrofuran, at a temperature from about OOC to about 100 0 C, preferably from about 250C to about 100 0 C. The 0

II

reactants in which R' is -C-W may be obtained by c xidation of the corresponding compounds wherein R' is -CHOHW as descril od above for the oxidation of compounds wherein H 1 is -CHOHR 6 Similarly, those compounds wherein R' is -CHOHW may be obtained by the procedure described above and depicted in scheme 1 for preparing the analogous compounds wherein R' is -CHOHR 6 or -CHOHR 7 Compounds of the formula IA wherein R 1 is a group of the formula WO 94/07867 PCT/US93/06446 -33- 1 6 may be formed by hydrogenation of the corresponding compounds wherein R' is W

Z

0 In the presence of a metal containing catalyst. Suitable hydrogenation catalysts include palladium, platinum, nickel, platinum oxide and rhodium. The preferred catalyst for hydrogenation is platinum on carbon. The reaction temperature may range from about 1000C to about 50C0, with about 25oC being preferred. The hydrogenation is generally carried out at a pressure from about 1.5 to about 4 atmospheres, preferably at about atmospheres, in a suitable inert solvent such as acetic acid or a lower alcohol, preferably methanol, with about a stoichlometric quantity of hydrogen chloride present.

Compc jnds of the formula IA wherein R is optionally substituted aryl, optionally substituted heteroaryl, dlhydroxy-(C,C 6 ,)alkyl or (C,-C 0 )alkyl-S-(C,-Cejalkyl may be prepared according to the reaction sequence illustrated and scheme 3. This reaction sequence is the same as that described in European Patent App ications 470616A2 and 384370A1, referred to above, with the exception that a compound of the formula

R'C=NHNH

2 wherein R' is defined as above, is used as a starting material. The conditions, reagents and catalysts, etc. used in the reactions of scheme 3 are set forth in detail in the foregoing patent applications, which, as indicated above, have been Incorporated herein by reference in their entirety.

Referring to scheme 3, a compound of formula II or its acid addition salt is reacted with a compound of formula III to give a compound of formula IV. The reaction is generally conducted or an alcoholic solvent such as methanol, ethanol or tertbutanol, at a temperature from about 250C to about 1000C, preferably from about 2500 to about 5QC 0 0 When an acid addition salt of a compound of formula II Is employed, the reaction is generally conducted as above in the presence of an alkali WO 94/07867 PCT/US93/06446 -34metal or alkaline earth metal hydroxide sodium, potassium, or calcium hydroxide) or an alkali metal alkoxide sodium or potassium ethoxldo or tert-butoxide) at temperatures ranging from about 1000C to about 80oC, preferably at temperatures between 300 and 600C.

The compound of formula IV is converted Into a pyrimidine derivative of the formula V by reacting it with an Inorganic acid chloride, phosphorus oxychloride, thienyl chloride, phosphorus pentachloride or phosphorous trichloride. This reaction is usually conducted in an aromatic hydrocarbon solvent, benzene, toluene or xylene, at a temperature from about 30° to about 100°C. The preferred temperature r..nge is between 300 and 600C.

Reaction of the compound of formula V with the appropriate compound of formula NHR 2

R

3 yields a compound of formula IA. Suitable solvents for this reaction Include ethereal solvents such as ethyl ether, tetrahydrofuran, or dioxane and halocarbon! solvents such as methylene chloride or chloroform. The reaction temperature may range from about 000C to about 80°C. Preferably, the solvent is a halocarbon solvent and the temperature is between OOC and 500C.

Compounds of the formula IA wherein R' is (C,-Co)alkoxycarbonyl-(C,-Cg)alkyl may be prepared by reacting the corresponding compounds wherein R' is hydroxy-(C,- Ce)alkyl with the appropriate (C 1 -C,)alkanoic acid chloride in the presence of an organic base. Examples of suitable organic bases are (C,-Co)alkylamines and dialkylamines, pyridine, quinoline and isoquinoline. Generally, this reaction is carried out in another or halocarbon solvent such as diethyl ether, tetrahydrofuran (THF), methylene chloride or chloroform, at a temperature from about 0°C to about 500C, preferably from about 0 C to about room temperature.

Compounds of the formula IA wherein R' is (C,-C)alkoxycarbonylaryl can be prepared In a similar manner, using the appropriate aroyl chloride in place of a C,)alkanolc acid chloride.

Compounds of the formula IA wherein R 1 is (C,-C,)alkyl-SO-(C,-Ca)alkyl may be prepared by oxidation of the corresponding compounds wherein R 1 is (C,-Cg)alkyl-S- (C,-Cg)alkyl using methods well known to those skilled in the art. For example, these oxidations may be conducted using m-chloroperbenzoic acid as the oxidizing agent in a halocarbon solvent such as methylene chloride or chloroform, at a temperature from about -1000 to about 100C, preferably about 0' Similarly, compounds of the WO 94/07867 PCT/US93/06446 formula IA wherein R' Is (C 1 -C,)alkyl-SO,-(C-C,)alkyl may be prepared by oxidation of the corresponding compounds wherein R 1 is (C,-C,)alkyl-SO-(C,-Ca)alkyl using methods known in the art. Such oxidations may be conducted, for example, in the manner specified above, but at a temperature ranging from about room temperature to about 600C, preferably at about the reflux temperature of the solvent.

Compounds of the formula VI can be prepared using methods that are well known in peptide chemistry. Some of these procedures are described below.

0

II

Compounds of the formula VI wherein R 25 isY'-C-O-Y 2 and Y' is absent can be 0 O 11 prepared as follows. A compound of the formula Y 3 -C-OH is first converted into 0

II

itscorresponding acid chloride, Y 3 -C-CI, by reacting it with thionyl chloride in a suitable aromatic or halocarbon solvent benzene, toluene, xylene, methylene chloride or chloroform), at a temperature from about 00C to about 1300C, preferably from about 0 C to about 1000C. The acid chloride is then reacted with a compound having the following formula R2 R 3

\N/

N R 5

XX

HO I N R 4

R

8 to produce the corresponding compound of formula VI wherein Y 2 is absent. This reaction is generally carried out in a halocarbon, aromatic hydrocarbon or ethereal solvent at a temperature from about 000 to about 15000, preferably from about 00C and about 1000C. Preferred solvents include benzene, toluene, xylene, methylene chloride, chloroform, ether, tetrahydrofuran and dioxane.

WO 94/07867 PCT/US93/06446 -36- Alternatively, compounds of the formula VI wherein Y 2 is absent can be prepared 0

II

by reacting a compound of the formula Y 3 -C-OH with a (C 4 -C )alkylchloroformate in the presence of any organic base, and then adding a compound of the formula XX, as depicted and defined above, to the reaction mixture. Examples of bases that may be used are (C 3 -Ce)alkylamines and aromatic amines such as pyridine, quinoline or isoqulnoline. This reaction is typically conducted in a halocarbon solvent, preferably methylene chloride or chloroform, at a temperature from about -7000 to about 500C, preferably from about -700C to about 200C.

The addition of the compound of formula XX is typically carried out at temperatures ranging from about -700C to about 50°C, preferably from about -700C and about 300C.

0 0 II II Compounds for the formula VI wherein R 25 is Y 3 -C-0-Y 2 and Y 2 is can be prepared by the following procedure. A compound of the formula XX, as depicted and defined above, is reacted with phosgene, to obtain a compound of the formula R2 R 3

\N

N

XX

0 2 8 N R 4 0-C-0-CL This reaction is conducted In the presence of a base a (C 3 -Co)alkylamine or an aromatic amine such as pyridine, quinoline or isoqulnoline) at a temperature from about -7000 to about 0°C, preferably from about -3000 to about 0°C. Appropriate solvents include ethereal, halocarbon and hydrocarbon solvents. Ether, dioxane, tetrahydrofuran, pentane, hexane, methylene chloride and chloroform are preferred.

The compound of formula XXI formed in the above reaction is then reacted with a 0 compound of the formula Y 3 -C-OH in the presence of a base a (C 3 -Co)alkylamine WO 94/07867 PCT/US93/06446 -37or an aromatic amine such as pyridine, quinoline or isoquinoline). The reaction is generally conducted at a temperature ranging from about -200C to about room temperature, preferably between about -100C and about room temperature, in a halocarbon or ether solvent, preferably in methylene chlor de or chloroform.

0 Y4 0 II I 11 Compounds of the formula VI wherein R 25 is Y 3 -C-0-Y 2 and Y 2 is may 0

II

be prepared in the following manner. First, a compound of the formula Y 3 -C-OH is contacted with an Ameberlite® IRA-904 resin containing quaternary ammonium groups in the hydroxide form to yield a salt of the formula 0 Resin II I

Y

3

+N(CH

3 3 (hereinafter referred to as a salt of the formula XXII). Usually, the 0

II

compound of formula Y 3 -C-OH is dissolved in a lower alcohol or hydrocarbon solvent such as ethanol, diethyl ether or hexane and the reaction is carried out at a temperature from about 100C to about 5000C, preferably at abrut room temperature.

Then, a compound having a formula identical to formula VI except that R 25 is replaced by a hydroxy group is reacted with a compound of the formula

Y

4

Y

4 I I CI-CH-COCI or Br-CH-COCI wherein Y 4 is hydrogen or (C,-Cs)alkyl, in the presence of an organic base. Bases that may be used include (C4-Clo)alkylamines and dialkylamines, pyridine, quinoline and isoquinoline. Suitable solvents include ether and hydrocarbon solvents puch as diethyl ether, methylene chloride, tetrahydrofuran and chloroform. Reaction temperatures may range from about OOC to about 50 0 C, and are preferably between about 0 0 C and about room temperature, The foregoing reaction produces a compound of the formula VI wherein R 2 5 is 0 Y 4 0 Y 4 II I II I -0-C-CH-CI or -0-C-CH-Br, which is then reacted with the salt of formula XXII to produce the desired compound of formula VI. This reaction is generally conducted in an ether, halocarbon or hydrocarbon solvent diethyl ether, hexane, methylene WO 94/07867 PCT/US93/06446 -38chloride or chloroform) at a temperature from about room temperature to about 60 C, preferably at about room temperature.

0

II

Compounds of the formula VI wherein R 2 5 is 02NH 2

CO

2

S-R

2 -HN-C-0- may be prepared by reacting a compound of the formula

R

2

R

3

\N/

1-C-O-CH^

N

with a compound of the formula OzNCH 2

SO,-R

26

-NH

2 Typipally, this reaction is carried out in an ethereal, halocarbon or hydrocarbon solvent at temperatures from about -700C to about 0 0 C. Preferably, it is carried out in ether, tetrahydrofuran, dioxane, hexane, pentane, methylene chloride or chloroform at a temperature from about -30 0 C to about 0 0

C.

Alternatively, such compounds can be prepared by reacting an isocyanate of the formula

H

3

C

OgN-CH2-SO,

N=C=

O

XXIII

H

3

C

with a compound of the formula XX, as depicted and defined above. Suitable and preferred solvents for this reaction are similar to those specified for the preceding reaction. This reaction is usually conducted at a temperature ranging from about ambient temperature to about 150 0 C, preferably from about ambient temperature to about 100 0

C.

The starting material of the formula XXIII can be prepared from the compound WO 94/07867 PCT/US93/06446 -39-

H

3

C

0 2

N-CH

2 -SO2 NH 2

H

3

C

using standard methods described in the scientific literature.

In each of the reactions discussed or illustrated above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about atmospheres are generally acceptable, and ambient pressure, about one atmosphere, is preferred as a matter of convenience. Reaction times also are not critical unless otherwise indicated. Reaction times from about 0.5 hours to about 3 hours are generally acceptable, though longer reaction times 24 or 48 hours) may be employed as a matter of convenience. Reaction times are monitored by thin layer chromatography.

The pharmaceutically acceptable acid addition salts of the compounds of the formulae I and VI that are basic in nature may be prepared in a conventional manner by treating a solution or suspension of the free base of formula I or VI with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts.

The pharmaceutically acceptable base addition salts of compounds of the formulae I and VI that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods. Thus, these salts may be readily prepared by treating the compound of formula I or VI with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the compound of formula I or VI may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.

Compounds of the formula I, the pharmaceutically acceptable salts of such compounds, mutual prodrugs of such compounds and aldose reductase inhibitors (including the mutual prodrugs of the formula VI), the pharmaceutically acceptable salts of such mutual prodrugs, and compositions comprising a compound of the formula I WO 94/07867 PCT/US93/06446 or a pharmaceutically acceptable salt thereof and an aldose reductase inhibitor or a pharmaceutically acceptable salt thereof (including compositions containing a compound of the formula I and a compound of the formula XV, XVI, XVII, XVIII or XIX) are hereinafter referred to, collectively, as "the active compounds and compositions of this invention".

The active compounds and compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. In general, compounds of the formula I and their pharmaceutically acceptable salts will be administered orally or parenterally at dosages between about 0.1 and about 50 mg/kg body weight of the subject to be treated per day, preferably from about 0.1 to 15 mg/kg, in single or divided doses.

Mutual prodrugs of compounds of the formula I and aldose reductase inhibitors will generally be administered orally or parenterally at dosages between about 5 and about 100 mg/kg body weight of the subject to be treated per day, preferably from about to about 25 mg/kg, in single or divided doses. Compositions containing both a compound of the formula I and an aldose reductase inhibitor will generally be administered orally or parenterally at dosages between about 1 and about 100 mg of each active component the compound of formula I and the aldose reductase inhibitor) per kg body weight of the subject to be treated per day, preferably from about 1 to about 25 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The active compounds and compositions of this invention may be administered alone c in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compounds of this invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium WO 94/07867 PCT/US93/06446 -41carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinyipyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar e'.d high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein m* bo combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions of the active compounds and compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable ior intravenous, Intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

The active compounds and compositions of this invention may be more particularly employed in the preparation of ophthalmic solutions. Such ophthalmic solutions are of principal interest for the treatment of diabetic cataracts by topical administration. For the treatment of diabetic cataracts, the active compounds ar.d compositions of this invention are administered to the eye in the form of an ophthalmic preparation prepared in accordance with conventional pharmaceutical practice. The ophthalmic preparation will contain a compound of the formula I, a mutual prodrug of a compound of the formula I and an aldose reductase inhibitor, or a pharmaceutically acceptable salt of such compound of formula I or prodrug, in a concentration from about 0.01 to about 1% by weight, preferably from about 0.05 to about in a pharmaceutically acceptable solution, suspension or ointment. In opthalmic preparations containing a combination of a compound of the'formula I and an aldose reductase inhibitor, each active ingredient will be present in an amount from about WO 94/07867 PCT/US93/06446 -42- 0.005 to about 1% by weight, preferably from about 0,005 to about 0.25%, in a pharmaceutically acceptable solution, suspension or ointment.

EXAMPLES

General Experimental Procedure Male Sprague-Dawley rats (350-400 g) were used for these experiments.

Diabetes was induced in some of the rats by a tail vein injection of streptozocin, mg/kg. Twenty-four hours later, 4 groups of diabetic rats were given a single dose of 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine (10, 50, 100, or300 mg/kg) by oral gavage. Animals were sacrificed 4-6 hours after dosing and blood and sciatic nerves were harvested. Tissues and cells were extracted with 6% perchloric acid.

Sorbitol in erythrocytes and nerves was measured by a modification of the method of R. S. Clements et al. (Science, 166: 1007-8, 1969). Aliquots of tissue extracts were added to an assay system which had final concentrations of reagents of 0.033 M glycine, pH 9.4, 800 pM B-nicotine adenine dinucleotide, and 4 units/ml of sorbitol dehydrogenase. After incubation for 30 minutes at room temperature, sample fluorescence was determined on a fluorescence spectrophotometer with excitation at 366 nm and emission at 452 nm. After subtracting appropriate blanks, the amount of sorbitol in each sample was determined from a linear regression of sorbitol standards processed in the same manner as the tissue extracts.

Fructose was determined by a modification of the method described by M.

Ameyama, Methods in Enzymoloqy, 89: 20-25 (1982). Resazurin was substituted for ferricyanide. Aliquots of tissue extracts were added to the assay system, which had final concentrations of reagents of 1.2 M citric acid, pH 4.5, 13 pM resazurin, 3.3 units/ml of fructose dehydeogenase and 0.068% Triton X-100. After incubation for minutes at room temperature, sample fluorescence was determined on a fluorescence spectrophotometer with excitation at 560 nm and emission at 580 nm. After subtracting appropriate blanks, the amount of fructose in each sample was determined from a linear regression of fructose standards processed in the same manner as the tissue extracts.

SDH activity was measured by a modification of the method described by U.

Gerlach, Methodology of Enzymatic Analyses, edited by H. U: Bergmeyer, 3, 112-117 (1983). Aliquots of sera or urine were added to the assay system, which had final concentrations of reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM NAD, W"O 94107867 PCT/US93/06446 -43mM sorbitol, and 0.7 units/ml of sorbitol dehydrogenase. After incubation for minutes at room temperature, the average change in sample absorbance was determined at 340 nm. SDH activity was presented as milliOD 3 40 units/minute (OD 340 optical density at 340 nm).

RESULTS

As shown in Figure 1, 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine ("Compound dose dependently lowered erythrocyte (red blood cell "RBC') fructose in diabetic rats. It dose dependently raised erythrocyte sorbitol in diabetic rats (Figure A similar lowering of fructose with an increase in sorbitol was seen in the sciatic nerve of diabetic rats (Figures 3 and 4).

This pattern of lowered fructose coupled with elevated sorbitol is consistent with that expected of an inhibitor of sorbitol dehydrogenase (SDH), the enzyme that converts sorbitol to fructose. However, when tested directly on sorbitol dehydrogenase in vitro, 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine exhibited an ICso value of 0.5mM. On the other hand, we discovered that sera from rats dosed with dimethylsulfamoyl)-piperazino]-2-methylpyriridine potently inhibited SDH in vitro in a dosa dependent manner (Figure The urine of animals dosed with 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2methylpyrimidine also potently inhibited SDH in vitro in a dose dependent manner (Figure Comparison with results for the sera (Figure 5) shows that the urine was an even more potent source of SDH inhibitory activity, with strong inhibition of SDH four d with as little as 0.5 pl of urine.

EXAMPLES 1, 2 and 3 Example 1: 4-f4-(N-methvlsulfamovl)-piperazinol-2-methvlpyrimidine Example 2: 4-[4-N-methylsulfamovl)-piperazino]-2-hvdroxy-methvlpyrimidine Example 3: 4[4-N-sulfamoyl)-piperazinol-2-methylpyrimidine An aqueous suspension of 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2methylpyrimidine ("Compound prepared as described in European Patent Application 384,370A1, was administered by oral gavage to male CD rats (350-430 g body weight) at a dose of 100 mg/kg. The rats were housed in appropriate cages and their urine (220 mL) was collected overnight. The urine was extracted with ethyl acetate mL) and the resulting emulsion was filtered through a supercel pad and the filtrate was collected. The ethyl acetate layer was separated and the aqueous layer was WO 94/07867 PCT/US93/06446 -44extracted again (3 x 75 mL). The ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate to obtain a crude oily residue (0.8 This residue was dissolved in 10 mL of a 9:1 mixture of methylene chloride and ethanol and chromatographed using a Chromatotron. The Chromatotron plate was eluted with a mixture of 19:1 of methylene chloride and ethanol and fractions were collected in 5 mL portions. Evaporation of the first 20 x 5 mL portions gave the title compound of Example 1 (6.9 mg): 1 H NMR (DMSO, 500 MHz) 6 2.37 3H), 2.55 J=7 Hz, 3H), 3.13 4H), 3.7 4H), 6.68 J=8 Hz, 1H), 7.72 1H), 8.13 J=8 Hz, 1H).

The next 20 x 5 mL portions yielded the title compound of Example 2 (24 mg): 'H NMR (DMSO, 500 MHz) 6 2.48 J=7 Hz, 3H), 3.1 4H), 3.58 4H), 4.36 2H), 6.1 1H), 6.33 J=8 Hz, 1H), 6.5 1H), 8.03 J=8 Hz, 1H). The last 20 x 5 mL portions gave the title compounds of Example 3 (15 mg): 1 H NMR (DMSO, 500 MHz) 6 2.34 3H), 3.04 4H), 3.65 4H), 6.35 J=8 Hz, 1H), 7.93 J=8 Hz, 1H).

EXAMPLE 4 414-(N,N-Dimethvlsulfamovl)piperizinol-2-hydroxymethylpyrimidine The title compound was prepared as described in European Patent Application 470,616A2, published February 12, 1992.

The structures and IC 50 values of 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2methylpyrimidine and the title compounds of Example 1-4 are set forth in Table I below.

The IC 50 values indicate the concentration at which fifty percent inhibition of sorbitol dehydrogenase i vitro was observed.

TABLE I I0 2 N(CH 3 2

N

N

CH

3 O 2

NCH

3 §O 2

NHCH

3 S0 2

NH

2

SO

2

N(CH

3 2

I

N

N CH 2 0H 4-14-(NN-dimethylsulfamoyt)- (Example 4) piparazinoI-2-methylpyrimidine (Compound 1) 1C 50 (uM) 480 (Example 1) (Example 2) (Example 3) 0.14 WO 94/07867 WO 9407867PCr/US93/06446 -46- EXAMPLE 4 4-N NDmtyslaolppeznlymdn--~mthl4dhIo4oo -b~enzothiazolvll -m ethl]- 1 -12hthalazine acetate A solution of 3,4-dihydro-4-oxo-3-[[(5-trifluoromethyl)-2-benzothiazolyll-methyl- 1-phthalazineacetic acid (839 mg, 2 mmol) in methylene chloride (10 ml-) containing triethylamine (0.28 2 rnmol) was added to a solution of isobutyl chloroformate (0.2 mL, 2 mmol) in methylene chloride (10 mL) at a temperature between -780 and -e50 C.

After 30 minutes, a solution of 4[4-(N,N-dimethylsulfamoyl)pipei-.zino]-2hydroxymethylpyrimidine in methylene chloride (5 ml-) was added to the reaction mixture. The reaction was allowed to warm to roomn temperature, stirred for 2 hours arid then quenched with water (20 mL). The methylene chloride layer was collected and was washed succesively with 5% sodium bicarbonate solution and water. T*he organic layer was dried, evaporated and the residue was chromatographed over silica gel. Elution with a solution of meth~rlene chloride in methanol (95:5) and evaporation of the eluent gave the title compound (0.35 M.P. 97-990C.

Claims (14)

1. 2. A pharmaceutical composition according to claim 1, wherein the compound of formula I is a compound wherein R 1 is (Cp-C 6 )alkoxycarbonyl-(C 1 -C 6 )alkyl, (C -C 6 )alkyl-S-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-SO-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-SO 2 (C -C 6 )alkyl dihydroxy-(C -C 6 )alkyl, aryl, heteroaryl, heteroaryl-(C 1 -C 6 )alkyl, aryl- (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, aryl-(Cl-C 6 )alkyloxy or heteroaryl- (C 1 -C 6 )alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C 1 -C 6 )alkyl, S 15 (C 1 -C 6 )alkoxycarbonylaryl, and aryl-(C 1 -C 6 )alkyloxy are independently selected from 'phenyl and naphthyl, and wherein said heteruaryl and the heteroaryl moieties of said Sheteroaryl-(C 1 -C 6 )alkyl and heteroaryl-(C 1 -C 6 )alkyloxy are independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, 20 oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkyl, (C 1 -Cs)alkoxycarbonylaryl, aryl-(C 1 -C 6 )alkyloxy and heteroaryl-(C 1 -C 6 )alkyloxy may optionally be substituted with one or more substituents independently selected from chloro, bromo, (C 1 -C 6 )alkyl, (Ct-C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, -SO-(Cj-C 6 )alkyl, -SO 2 25 (C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl and trifluoromethyl.
2. 3. A pharmaceutical composition according to claim 1, comprising an amount of said compound of the formula I that is effective in inhibiting the enzyme sorbitol dehydrogenase,
3. 4. A pharmaceutical composition according to claim 1, comprising an amount of said compound of the formula I that is effective in lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes. A pharmaceutical composition according to claim 1, comprising an amount of said compound of the formula I that is effective in treating or preventing a diabetic complication in a mammal, [N:\Llluu]OlO36:KEH WO 94/07867 PCr/US93/06446 lb T A pharmaceutical composition according to claimp, wherein said diabetic complication is diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy or diabetic macroanglopathy. 7 -er.-A method of: inhibiting the enzyme sorbitol dehydrogenase in a mammal; lowering the level of fructose in onie or more of the tissues of a mammal that are affected by diabetes; or treating or preventing a diabetic complication in a mammal; comprising administering to said mammal an amount of a compound of the formula R2 R 3 R 3, N: R4 wherein RI is hydrogen, CE 3 (C,-C,)alkyl, (C 1 -C,)alkyl-S-(C,-C,)alkyl, (C 1 -C,)alkyl-SO- (C,-C,)alkyl, (C,-C,)alkyl-SO 2 -(Cl-C,)alkyl, hydroxy-(Cl-C,)alkyl, dihydroxy-(Cl-C 8 )alkyl, (C,-C,)alkoxy, (C,-C 8 )alkoxycarbonyl-(C,-C 6 )alkyl, aryl selected from phenyl and naphthyl, aryl-(C,-C 6 ,)alkyl wherein the aryl moiety is selected from phenyl and naphthyl, (C,-C,)alkoxycarbonylaryl wherein the aryl moiety is selected from phenyl and naphthyl, aryl-(C,-C,)alkyl wherein the aryl moiety is selected from phenyl and naphthyl, aryl.(C 1 C,)alkyloxy wherain 'the aryl moiety is selected from phenyl and napthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, and benzothienyl; heteroaryl-(Cl- C,)alkyl wherein heteroaryl is defined as above, or heteroaryl-(C,-C,)alkyloxy wherein heteroaryl is defined as above, and wherein said aryl and heteroaryl groups, the aryl moieties of said Mrl-(C,-C,)alkyl, (C 1 -C)alkoxycarbonylaryl and aryl-(C,-C,)alkyloxy and the heteroaryl moiety of said heteroaryl-(C,-C,)alkyl may optionally be substituted with one or more substituents independetitly selected from chloro, bromo, (C,-C,)alkyl, (Cl- C,)alkoxy, -S-(C 1 -C 6 )alkyl, -SO-(C 1 -C 6 )alkyl, -S0 2 -(C 1 -C,)alkyl, hydroxy-(C 1 -C, 0 )alkyl and trifluoromethyl; or RI is a group of the formula WO 94/07867 WO 9407867PCr/US93/ 06446 S~L ~S4~ G1 wherein the dotted line represents an optional double bond, W, Q and Z are independently selected from hydrogen, (C,-C,)alkyl and triflIuorom ethyl, phenyl, furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl, fury', triazolyl, thiazolyl and thienyl may optionally be substituted with one or more substituents Independently selected from (C 1 -C,,)alkyl, (Cl-C,)alkoxy, trifluoromethyl and hydroxy; 0 11 or RI is a group of the formula wherein R' Is hydrogen, (C,-C,)alkyl, aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl and benzothienyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, bromo, nitro, trifluorom ethyl, (C 1 -C 6 )alkoxy, -S-(C 1 -C,)alkyl, -SO-(C 1 -C6)alkyl and -S0 2 -(C 1 -C,)alkyl; or R1 is a group of the formula Y-0-CH-R wherein R 7 is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothienyl and qulnolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents Independently selected from chloro, bromo, (C,-C,,)alkyl, (C 1 -C,)alkoxy, -S(C 1 -C,)alkyl, SO-(C,-C,)alkyl, -S0 2 -(C,-C6)alkyl and triflu orom ethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, aryl selected from phenyl and naphthyl, heteroaryl selected from furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, bromo, nitro, trifluorom ethyl, -C,)alkyl, (C 1 -C,)alkoxy, -S-(C 1 -C 6 )alkyl, -SO-(C 1 -C 6 )alkyl and S0 2 -(C,-C,)alkyl; R 2 and RI are independentit' selected from hydrogen, (C 1 -C 6 )alkyl, phenyl and phenyl-(C 1 -C 4 )alkyl, wherein said phenyl and the phenyl moiety of said phenyl -(C 1 C 4 alkyl may optionally be substituted with one or more substituents independently L selected from (C,-C,)alkyl, (C 1 -C6)alkoxy, chloro, bromo and triflu orom ethyl; WO 94/07867 WO 9407867PCT/US93/06446 or RI and RI form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted with from zero to two substituents, independently selected from (Cl-C,)alkyl, -CONH 2 -SO 2 2 N-(C 1 C 4 )aikylsulfamoyl, N,N-di-(C 1 -C 4 )alkylsulfamoyl, (C 1 -C,)aikoxycarbonyl, N,N-di-(C 1 C 4 )aikylcarbamoyl, N-(C 1 -C 4 )alkylcarbamoyl, N-phenylcarbamoyl, 8 )alkylcar. bonyl, phenylcarbonyl, (C,-C,)alkyisulfonyl, (C,-C,)alkylsulfinyl, phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein the heteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonyl are selected from furyl, thienyl, thiazolyl, and oxazolyl, and wherein the phenyl moieties of said phenylcarbonyl, N-phenylcarnamoyl, phenylcarbonyl and phenylsulfonyl may optionally be substituted with one or more substituents independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, c'nloro, bromo, nitro, amino, cyano and trifluoromethyl; R 4 is hydrogen, chloro, bromo, cyano, nitro, triflu orom ethyl, amino, (C 1 -C,)alkyl, (C,.C,)hydroxyalkyl, (C,-C 6 ,)alkoxy, phenyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted with one or more substituents independently selected from chloro, bromo, trifluorom ethyl, (C,-C,)alkyl, (C 1 -C, 6 )alkoxy, S-(C 1 -C,)alkyl, alkyl, -S02-(Cl -C,,)alkyl and hydroxy; and RI is hydrogen, (Cl-C,)alkyl, (C,-C 8 )alkoxy, trifluoromethyl, -C, 6 )hydroxyalkyl, -SO-(C,-C,)alkyl, -S0 2 -(C,-C,)aikyl, phenyl orfuryl, wherein said phenyl and furyl may optionally be substituted with one or more substituents independently selected from chloro, bromo, trifluoromethyl, (C,-C,)alkyl, (C,-C,)alkoxy, -SO-(C 1 C,)alkyl, -S0 2 -(C,-C,)alkyl and hydroxy; or Ex pharmaceutically acceptable salt thereof, effective in, respectively: (a) inhibiting the enzyme sorbitol dehydrogenase; lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes; or treating or preventing a diabetic complication. method according to claim 4 wherein the compound of formula I that is employed is a compound wherein RI is (C 1 -C 6 )alkoxycarbonyl-(C 1 -C 6 )alkyl, (C,-C,)alkyl- S-(C 1 -C 6 )alkyl,(C,-C 6 )alkyl-SO-(Cl-C 6 )alkyl, (C,-C 6 )alkyl-S0 2 -(C 1 -C 6 )alkyl,dihydroxy-(C,- C,)alkyl, aryl, heteroaryl, heteroaryl-(C,-C,,)alkyl, aryl-(C,-C,)alkyl, (C 1 C 6 ,)alkoxycarbonylaryl, aryl-(C 1 -C,)alkyloxy or heteroaryl-(C 1 -C,)aikyloxy, wherein said 4 4\ aryl and the a~ryl moieties of said aryl-(C,-C 6 )alkyl, (C 1 -C 6 ,)alkoxycarbonylaryl, and aryl- 54 (C 1 -C 6 )alkyloxy are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moieties of said heteroaryl-(C 1 -C 6 )alkyl and heteroaryl- (C 1 -C 6 )alkyloxy are independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C 1 -C 6 )alkyl, aryl-(Ci-C 6 )alkyl, (CI-C 6 )alkoxycarbonylaryl, aryl-(C 1 -C 6 )alkyloxy and heteroaryl- (C 1 -C 6 )alkyloxy may optionally be substituted with one or more substituents independently selected from chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, -S-(CI-C 6 )alkyl, -SO-(CI-C 6 )alkyl, -S0 2 -C 6 )alkyl, hydroxy-(C -C 6 )alkyl and trifluoromethyl.
4. 9. A method according to claim 7 of inhibiting sorbitol dehydrogenase in a mammal. A method according to claim 7 of lowering the level of fructose in one or more of the tissues of a mammal that are effected by diabetes. i 11. A method according to claim 7 of treating or preventing a diabetic complication in a mammal.
5. 12. A method according to claim 11, wherein said diabetic complication is diabetic neuropathy, a diabetic vascular disease, microangiopathy or diabetic 20 macroangiopathy.
6. 13. A pharmaceutical composition according to claim 1 in unit dosage form.
7. 14. A pharmaceutical composition according to claim 1, in the form of a tablet suitable for oral administration.
8. 15. A pharmaceutical composition according to claim 1, in the form of a solution 25 for parenteral administration.
9. 16. A pharmaceutical composition according to claim 1, in the form of a solution *suitable for ophthalmic administration.
10. 17. A mutual prodrug of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, and an aldose reductase inhibiting compound.
11. 18. A compound of the formula [N:\LIBuu]01036:KEH WO 94/07867 WO 9407867PCT/US93/06446 R 8 N I Rv R 25 -CHA N 0 0 11 11 wherein R' 5 is Y 3 C0Y-or 0 2 NH 2 C0 2 S-R 2 eHNC0., and R 2 1 is aryl selected from phenyl and naphthyl, wherein said aryl may optionally be substituted with one or more substituents independently selected from chloro, bromo, (Cl.C, 6 )alkyl, (C,-C,,)alkoxy, -S- (C,-C 8 )alkyl,-SO-(C 1 -C 8 )alkyl, -S0 2 -(C 1 alkyl, hyd roxy- alkyl and triflIu oromethyl; R 2 and R' are independently selected f-rm hydrogen, (C,-C,,)alkyl, phenyl and phenyl-(C,-C 4 )alkyl, wherein said phenyl and the phenyl moiety of said phenyl C 4 )alkyl may optionally be substituted with one or more substituents independently selected from (C,-C,)alkyl, (C,-C,)alkoxy, chloro, bromo and trifluoromethyl; or R 2 and R 3 form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted with from zero to two substituents independently selected from (C,-Ce)alkyl, -CONH- 2 -SO 2 NH 2' C 4 )alkylsulfamoyl, N, N-di-(Ci-C 4 )alkylsulfamoyl, (C,-C,)alkoxycarbonyl, N, N-di-(C 1 C 4 )alkylcarbamoyl, N-(C 1 -C 4 )-alkylcarbamoyl, N-phenylcarbamoyl, (CI- C,)alkylcarbonyl, phenylcarbonyl, (C,-C 6 )alkylsuhonyl, 6 )alkylsulfinyl, phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein the heteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonyl are selected from furyl, thienyl, thiazolyl and oxazolyl, and wherein the phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl, phenylcarbonyl and phenylsulfonyl may optionally be substituted with one or more substituents independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, chloro, bromo, nitro, amino, cyano and trifluoro methyl; R' is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C,-C 6 ,)alkyl, (C 1 -C,)hydroxyalkyl, (C,-C,)alkoxy, phenyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted with one or more substituents independently selected from chloro, bromo, trifluoromethyl, (C 1 -C 6 )alkyl, (C 1 -Cr 6 )alkoxy, S-(C,-C,)alkyl, -SO-(C 1 -C 8 )alkyl, -S0 2 -(CI-Cr,)alkyl and hydroxy; WO 94/07867 WO 9407867PCT/US93/06446 R' is hydrogen, (C,-C,)alkyl, (Cl-C,)alkoxy, trifluoromethyl, (C,-C,)hydroxyalkyl, -S-(Cl-C,)alkyl, 5 )alkyl, -S0 2 -(C,-C,)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionally be substituted with one or more substitu: nts independently selected fromn chioro, bromo, trifluorom ethyl, (C,-C,)alkyl, (C,-C,,)alkoxy, 6 )alkyl, -SO-(C 1 -C,)alkyl, -S0 2 -(C 1 -C,,)alkyl and hydroxy; R' is hydrogen or R'; R 7 is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thlazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothienyl and quinolyl, whereirn said aryl and heteroaryl groups may optionally be substituted with ons or more substituents independently selected from chloro, bromo, (C,-C,,)alkyl, (Cl-C, 6 )alkoxy, 6 )alkyl, -SO-(Cl-0 6 )alkyi,, -S0 2 -(Cl- C,)alkyl arnd trifl uorom ethyl, and Y is hydrcgen, benzyl, acetyl, benzoyl, aryl .oelected from phenyl and naphthyl, or heteroaryl selected from furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, bromo, nitro, trifluoromethyl, (Cl-C,)alkyl, (C,-C,)alkoxy, -S-(C,.C,)alkyl, -SO-(C,-C 6 ,)alkyl and -SO 2 (C 1 -C,)alkyl; 0 y 4 0 11 1 11 VY- is or y 2 is absent the carbon to which R' is attached 0 is directly bonded to Y 3 CO) Y' is hydrogen or (Cl-C,)alkyl; and Y 3 is selected frtim the following groups: PCr/US93/O6446 WO 94/07867 R 1 2 R 13 N: S xiI I WO 94/07867 PCT/US93/06446 ST/ and R 12 0 SR13 (A XIVA B II wherein A is CH,, CHCH,, CH(CH,) or CH,-C-NH; B is oxygen or sulfur; R 9 is selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl-1,2,4-oxadiazol- and 5-phenyl-1 ,2,4-oxadiazol-3-yl, and R 9 may optionally be substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, methyl, methylthio, methoxy, hydroxy and trifluoromethyl; R'o and R" are independently selected from hydrogen, fluorine, chlorine, bromine, (C,-C 4 )alkyl, (C 1 -C 4 )alkylthio, (C,-C 4 )alkoxy and trifluoromiethyl; or R' 1 0 and R" together, with the carbons to which they are attached, form a group of the formula E E or (CHP O (CH) D F 212 wherein p is 1 or 2; D and E are independently selected from -CH 2 oxygen and sulfur, except that D and E cannot both be oxygen and cannot both be sulfur; R 12 and R' 3 are independently selected from hydrogen, fluorine, chlorine, bromine, (C,-C 4 )alkyl, (Ci- C 4 )alkylthio, (C,-C 4 )alkoxy and trifluoromethyl; and F and G are independently selected from -CH- and nitrogen; R 1 2 and R'" 3 are independently selected from hydrogen, fluorine, chlorine, bromine, (C,-C 4 )alkyl, (C 1 -C 4 )alkylthio, (C,-C 4 )alkoxy and trifluoromethyl; WO 94/07867 PCT/US93/06446 L6er- K is oxygen, sulfur, SO or SO2; R 14 is hydrogen, fluoro, chloro, bromo, methyl, nitr cyanc, methanesulfonyl or benzoyl; is hydrogen, fluoro, chloro, bromo, carboxy, (C,-C 3 )alkyl, (C,-C 3 )alkoxy or benzyloxy; R 1 6 is hydrogen, fluoro, chloro, bromo or (C,-C 3 )alkyl; or R 1 5 and R' 6 together with the carbon atoms to which they are attached, form a 7,8-benzo ring; R' is (C;-C 4 )alkyl, trifluoromethyl or (CH 2 wherein n is 0, 1 or 2 and Ar is phenyl optionally substituted with one or two substituents independently selected from methoxy, fluoro, chloro and bromo; R 1 is hydrogen, methyl or ethyl; or R' 7 and R' 8 together with the carbon to which they are attached, form a saturated 4 or 5 membered carbocyclic spiro ring; and R' 9 is hydrogen or methyl; with the proviso that: when K is other than oxygen, R 1 4 is fluoro, chloro, cyano or nitro, and R' 5 and R'I do not form a 7,8-benzo ring; when K is other than oxygen or R 1 7 is other than methyl, ethyl or trifluoromethyl, both R" 8 and R' 9 are hydrogen; and when Y 3 is a group of the formula XIVA, R 9 is benzothiazol-2-yl or substituted benzothiazol-2-yl; or a pharmaceutically acceptable salt of such compound. 0 \II (WfC A compound according to claim O wherein R 2 5 is Y 3 C-O-Y 2 Y 2 is not absent and: Y 3 is a group of the formula VII, R 9 is phenyl, substituted phenyl, benzothiazci-2-yl or benzoxazol-2-yl, A is -CH 2 and R 10 and R" are either both methyl or they form, together with the carbons to which they are attached, a group of the formula SOR ~L I WO 94/07867 PCT/US93/06446 -62- Y 3 is a group of the formula VIII, R 9 is phenyl, substitu"ed phenyl, benzothiazol-2-vl or benzoxazol-2-yl, A is -CH 2 and R 12 and R' 3 are independently selected from bromo and chloro; Y 3 is a group of the formula IX and each of R 12 and R 1 3 is hydrogen; (d) Y 3 is a group of the 'form;la X and R' 2 and R 1 3 are independently selected from C,)alkoxy and trifluoromethyl; Y 3 is a group of the formula XI anrd R 1 2 and R 13 are independently selected from (C,-C 6 )alkyl; Y 3 is a group of 'ihe formula XII, R 9 is phenyl, substituteu phenyl or benzothiazol-2-yl, A is and R 1 2 and R 13 are independently selected frci chloro and bromo; or Y 3 is a group of the formula XIII, each of and R" 1 is hydrogen, each of R" and is methyl, R 1 is 6-chloro or 6- fluoro and R 1 6 is 7-chloro or 7-fluoro.
12. 22. A pharmaceutical co~~nposition comprising a-paFaeetieally acceptabl. carrier and an amount of a mutual prodrug of a compound according to claim nd an aldose reductase inhibiting compound, or a pharmaceutically acceptable at of such a prodrug, that is effective in inhibiting the enzyme sorbitol de drogenase, (b) lowering the level of fructose in one or more of the tissues a mammal that are affected by diabetes, or treating or preventing a diab t complication in a mammal.
13. 23. A method of: inhibiting the e zme sorbitol dehydrcgenase in a mammal; lowering the level of fructosej one or more of the tissues of a mammal that are affected by diabetes; or ting or preventing a diabetic complication in a mammal; comprising administ iig to said mammal an amount of a mutual prodrug of a compound according claim 1 and an aldose reductase inhibiting compound, or a pharmaceutically ceptable salt of such a prodrug, that is effective in, respecti'. ly: (a) inhibiting th nzyme sorbitol dehydrogenase, lowering the level of fructose in one or m of the tissues of a mammal that are affected by diabetes, or treating or anting d c ompli n
14. 70-24 A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of a mutual prodrug of an aldose reductase inhibiting compound and a compound of the formula I, as lefined in claim-, 'r a pharmaceutically acceptable salt of such a prodrug, that is effective in inhibiting the enzyme sorbitol dehydrogenase, lowering the level of fructose in one or mors of the tissues of a mammal that are affected by diabetes, or treating or preventing a diabetic complication in a mammal. I 21. A method of: inhibiting the enzyme sorbitol dehydrogenase in a mammal; lowering the level of fructose in one more of the tissues of a mammal that are affected by diabetes; or treating or preventing a diabetic complication in a mammal; comprising administering to said mammal an amount of a mutual prodrug of an aldose 6 reductase inhibiting compound and a compound of the formula, as defined in claim 1, or a pharmaceutically acceptable salt of such a prodrug, that is effective in, respectively; (a) inhibiting the enzyme sorbitol dehydrogenase, lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes, or treating or preventing a diabetic complication in a mammal. 22. A pharmaceutical composition comprising: an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissue s of a mammal, that are affected by diabetics; an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes; and a pharmaceutically acceptable carrier. 23. A method of lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes, comprising administering to said mammal a fructose lowering effective amount of a compound of the formula I, as defined in claim 1, 20 or a pharmaceutically acceptable salt thereof, in combination with a fructose lowering effective amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising an amoumi of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, effecting in 25 treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal; an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof effecting in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy or diabetic microangiopathy or macroangiopathy in a mammal; and a pharmaceutically acceptable carrier. A method of treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or IN:\LIBuu01-036:KE lN:\Ll3u)01036;KBHI macroangiopathy in a mammal, comprising administering to said manunal an amount of a compound of the formula I, as defined in claim 2, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication, in combination with an amount of an aldose reductase inhibiting compound, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication. 3 A pharmaceutical composition comprising: an amount of a compound of the formula I, as defined in claim 2, or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetics; an amount of a compound of the imula: 0S cu *00 C 0e C 10 S XV, XVI, 6S *c e 0@e S *000 0 00 6 XVII, XVIII and MSO 2 CH 2 NO 2 x XIX 0 'S 0 OS [N\LIBCj00756:JOC WO 94/07867 WO 4/7867 Cr/US93/06446 0 11 wherein L Is oxygen, OH 2 sulfur or 0 11 J Is hydrogen, methyl or H 2 GIs CH or N; R 20 and R 2 1 are Independently selected from hydrogen, fluorine, chlorine, (C 1 C,)alkyl, (C 1 -Ca)alkoxy, -S.(Cd 0 alkyl, .SO-(C 1 .C,)alkyl or -S0 2 .(C 1 .C 0 )alkyl; M is phenyl, naphthyi or a heteroaryl group selected from furan, morpholine, pyrrolidine, tetrahydrolsoqulnolint-, thiophene, thiazole, oxazole, benzofuran, benzothiophene, benzothlazole, benzoxazole and Indole, wherein said phenyl, naphthyl and heteroaryl groups may optionally be substituted with up to three substituents Independently selected from chioro, fluoro, bromo, cyano, nitro, hydroxy, carboxy, amino (C 1 -C,)alkylamino, (C 1 -0 0 )dlalkylamino, (C,-C,)aikanoylamino, (C,-C,)alkanoyl, (C 1 -C 0 aikyl, C 2 -C 0 )alkenyi, (C 3 -C 6 )alkenyloxy, fluoro-(C,-C 0 )alkyl, (C,-C,)alkoxy, fluoro- (C 1 -C4alkoxy, -C,)hydroxyalkyl, carbamoyl, (C 1 -C 7 )alkylcarbamoyl, (Cl- C 7 )dialkyicarbarnoyl, sulfamoyl, (C 1 -C 0 alkysuifamnoyl, (C 1 -C 0 )dlaikylsuifamoyl, (C 1 C.)aikoxycarbonyl, (C 1 -C 4 )alkylenedioxy, (C 1 -C,)alkanesuffonamldo, -S-(C 1 -C,)alkyl, -SO- (C,-C,)alkyl, -S0 2 -(C 1 .C,)alkyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamldo, and benzenesulfonamido, and wherein said phenyl and the phenyl moieties of said phenoxy, benzyloxy, benzyioxycarbonyl, benzamido and benzenesulfonamldo may optionally be substituted with a substituent selected from chlorine, fluorine, (Cl- C 4 )alkyl (C,-C 4 )alkoxy and 0 R 22 -N-C-C-Y R 2 3 wherein Y1 Is oxygen or sulfur, or Yr, Is absent the phenyl ring Is bonded to the carbon to which R 22 and R 23 are attached), and R 2 2 and R 23 are Independently selected from hydrogen and (C,-C 4 )alkyl, and the phenyl moiety to which the -NHCOC(R 2 2 )(R 23 Yl- sidechain is attached may optionally be substituted with from one to three substituents Independently selected from hydrogen, haio, trifluoromethyl, nitro, cyano, WO 94/07867 WO 9407867PCI'/US93/06446 K- M Is phenyl, naphthyi or a heteroaryi group selected from furan, morpholine, pyrroildine, tetrahydroisoqunoline, thiophene, thiazole, oxazole, benzofuran, benzothlophene, benzothiazole, benzoxazoie and indole, wherein said phenyl, naphthyl and heteroaryl groups may optionally be substituted with up to three substituents Independently selected from chioro, fluoro, bromo, cyano, nitro, hydroxy, carboxy, amino akylamino, (0 1 -C)dlalkylamlno, (C 1 -C,)alkanoylamlno, (C,-C 0 alkanoyl, (C 1 -C,)alkyl. (C 2 -C,)alkenyl, (C 3 -C 0 )alkenyloxy, fluoro-(C 1 .C 0 )alkyl, (C 1 .C,)alkoxy, fluoro- (C 1 -C 4 )alkoxy, (C 1 -C 6 )hydroxyalkyl, carbamoyl, (C 1 -C 7 )alkylcarbamoyl, (C 1 C 7 )dialkyicarbamoyl, sulfamoyl, (C,-C,)alkysulfamoyl, (C,-C,)dialkylsulfamoyl, (C 1 C 6 )alkoxycarbonyl, (C 1 -C 4 )alkylenedloxy, (C 1 -C 6 )alkanesulf onamido 1 -C,)alkyl -SO- (C 1 -CO)alkyl, -S0 2 -(CI-C,,)alkyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido, and benzenesulfonamldo, and wherein said phenyl and the phenyl moieties of said phenoxy, benzyloxy, benzyloxycarbonyi, benzamido and benzenesulfonamido may optionally be substituted with a substituent selected from chlorine, fluorine, C4)alkyl (C,-C 4 )alkoxy and 0 R 22 -N-C-C -Y' R 2 3 wherein Y' Is oxygen or sulfur, or Y 5 Is absent the phenyl ring is bonded to the carbon to which R 22 and R 2 are attached), and R 2 2 and R 23 are independently selected from hydrogen and (C 1 -C4)aikyl, and the phenyl moiety to which the -NHCOC(R' 2 (R 23 sidechain Is attached may optionally be substituted with from one to three substtuents Independently selected from hydrogen, halo, trifluo rom ethyl, nitro, cyano, (C 1 -C 4 )alkyl, (C,-C 4 )alkoxy and (C 1 -C 4 )aikanoyl, or any adjacent pair of substituents may form, together with the carbons to which they are attached, a benzo ring which may optionally be substituted with a substituent independently selected from halo, (C 1 C 4 )alkyl and (Ci-C4)aikoxy; s0 0 with the proviso that: when 'J is -C"nH 2 G is CH and L is oxygen; and M Is not 2-carboxyphenyl; or a pharmaceutically acceptable salt thereof, that is effective in lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes; and a pharmaceutically acceptable carrier. 27. A method of lowering the level of fructose in one or more of the tissues of a mammal that are affected by diabetes, comprising administering to said mammal a fructose lowering effective amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a fructose lowering effective amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, as defined in claim 26, or a pharmaceutically acceptable salt thereof. 1o 28. A pharmaceutical composition comprising: an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal; an amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, as defined in claim 26, or a pharmaceutically acceptable salt thereof, effective in treating or preventing a diabetic complication such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy or diabetic microangiopathy or macroangiopathy in a manmnal; and a pharmaceutically acceptable carrier. 29. A method of treating or preventing a diabetic complication such as diabetic 20 neuropathy, diabetic retinopathy, diabetic nephropathy, or diabetic microangiopathy or macroangiopathy in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication, in combination with an amount of a compound of the formula XV, XVI, XVII, XVIII or XIX, as defined in claim S 25 26, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such complication. 30. A pharmaceutical composition according to claim 26, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, that is employed is a compound wherein R 1 is (C 1 -C 6 )alkoxycarbonyl-(C -C 6 )alkyl, (C 1 -C 6 )alkyl-S-(Ci-C 6 )alkyl, (Ci-C6)alkyl-SO-(Cl-C 6 )alkyl, (Ci-C 6 )alkyl-SO 2 -C 6 )alkyl, dihydroxy-(C -C 6 )alkyl, aryl, heteroaryl, heteroaryl-(Ci-C 6 )alkyl, aryl-(C -C 6 )alkyl, (C -C 6 )alkoxycarbonyl, aryl- (Ci-C 6 )alkyloxy or heteroaryl-(C 1 -C 6 )alkyloxy, wherein said aryl and the aryl moieties of said aryl-(Ci-C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylaryl, and aryl- [N:\LIBuu]01036:KEH I WO 94/07867 PCr/US93/06446 _Ge- (C, 1 C,)alkyloxy are Independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moieties of said heteroaryl-(Cl-C 6 )alkyl and heteroaryl-(C,- C,)alkyloxy are Independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C 1 -C6)alkyl, aryl-(C,-C,)alkyl, (C 1 -C,)alkoxycarbonylaryl, aryl-(C 1 -C, 6 )alkyloxy and heteroaryl-(C 1 C,)alkyloxy may optionally be substituted with one or more substituents independently selected from chloro, bromo, (C,-C,)alkyl, (C,-C,)alkoxy, -S-(C 1 -C,)alkyl, -SO-(C 1 C,)alkyl, -S0 2 -(C 1 -C,)alkyl, hydroxy-(0 1 -C,)alkyl and trifluoromethyl. A method according to claim2-3 wherein the compound of formula 1, or pharmaceutically acceptable salt thereof, that is employed, is a compound wherein III Is (C 1 -C,)alkoxycarbonyl-(C,-C 5 )alkyl, (C 1 -C,)alkyl-S-(C,-C,)alkyl, (C 1 -C,)alkyl-SQ-(C,- Ce)alkyl, -C,)alkyl-SO 2 -(Cl -C,)alkyl, dihydroxy-(C,-C,)aikyl, aryl, heteroaryl, heteroaryl- (C 1 -C 0 )alkyl, aryl-(C,-C,)alkyl, (C,-C,)alkoxycarbonylarl, aryl.(C 1 -C6)alkyloxy or heteroaryl-(C 1 -C,)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C,- C,)alkyl, (C,-C,)alkoxycarbonylaryl, and arll-(C,-C,)alkyloxy are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moieties of said heteroaryl-(C,-C,)alkyl and heteroaryl.(C,-C,)alkyloxy are independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C,-C,)alkyl, aryl-(C 1 -C 8 ,)alkyI, (C 1 alkoxycarbo nylaryl, aryl-(Cl -C,,)alkyloxy and hetero aryl-(C, alkyioxy may optionally be substituted with one or more substituents independently salected from chloro, hydroxy-(CI -C 0 )alkyl and trifluorom ethyl.A9 3 Z-8&7- A pharmaceutical composition according to claim.32, wherein the compound of formula 1, or pharmaceutically acceptable salt thereof, that is employed, Is a compound wherein RI Is (C,-C)alkoxycarbonyl.(C 1 -C 0 )alkyl, (C,-C,)alkyl-S-(C,- C,)alkyl, (Cl-C,)alkyl-SO-(C 1 -C,)alkyl, (C 1 -C,,)alkyl-SO 2 -(C 1 -C,,)alkyl, dihydroxy-(C 1 CO)alkyl, aryl, heteroaryl, heteroaryl-(C,-C,)alkyl, aryl-(C 1 -C,)alkyl, (Cl- C,)aikoxycarbonylaryl, aryl-(C,-C,,)alkyloxy or heteroaryl-(C 1 -C,,)alkyloxy, wherein said WO 94/07867 WO 9407867PCr/US93/06446 aryl and the aryl moieties of said aryi-(CI-CO)alkyl, (C 1 -C,)alkoxycarbonylaryl, and aryl- (C,-C,)alkyloxy are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moieties of said heteroarl-(C, -C,)alkyl and heteroaryl.(C 1 C,)aikyloxy are Independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C,-C,)alkyl, aryl-(C,-C,)alkyl, (C 1 -Ce)alkoxycarbonylaryl, aryl-(C 1 -C 6 )alkyloxy and heteroaryl-(C 1 C,)alkyloxy may optionally be substituted with one or more substituents independently selected from chioro, bromo, (C,-C 6 ,)alkyl, (Cl-C,)alkoxy, -S-(C 1 -C,)alkyl, -SO-(C 1 C,)alkyl, -S0 2 -(C,-C,)alkyl, hydroxy-(Cl-C,)alkyl and trifl uorom ethyl. 33 A method according to cilm 32 wherein the compound of formula 1, or pharmaceutically acceptable salt thereof, that is employed, is a compound wherein R, is (C 1 -C 0 )alkoxycarbonyl-(C 1 -Ca)alkyl, (C 1 .CG)alkyl-S-(C 1 -C 6 )alkyl, (C 1 -C,)alkyl-SO.(C 1 C,)alkyl, (C,-C,)alkyl-S0 2 -(C 1 -C,)alkyl, dihydroxy-(CI-C,)alkyl heteroaryl, heteroaryl- (C,-C,)alkyl, aryl-(C,-C,)alkyl, (C,-C,)alkoxycarbonylaryl, aryl-(C 1 -C 6 ,)alkyloxy or heteroaryl-(C 1 -C 0 ,)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C,- C.)alkyl, (C 1 -C,)alkoxycarbonylaryl, and aryl-(C 1 -C 6 ,)alkyloxy are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moieties of said heteroaryl-(C,-C,)alkyl and heteroaryl-(C,-C,)alkyloxy are independently selected from wherein the aryl moiety is selected from phenyl and naphthyl, heteroaryl selected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C 1 -C 6 )alkyl, aryl-(C 1 -C.)alkyl, (C 1 C,)alkoxycarbonylarl, aryl.(C, .C,)alkyloxy and heteroaryl.(C, -C,)alkyloxymay optionally be substituted with one or more substituents independently selected from chloro, bromo, 6 )alkyl, (Ci.C,)alkoxy, 6 )atkyl, .SO-(C 1 .C,)alkyl, -S0 2 -(C,-C,)alkyl, hydroxy-(C 1 alkyl and trifluoromethyl. 68 34. A compound of the formula VI, substantially as hereinbefore described with reference to any one of the Examples. Dated 21 May, 1997 Pfizer Inc. Patent Attorneys for the Applicant/Nomninated Person SPRUSON FERGUSON V 0 0, 0 [N:ALIJuu]01036.:KEH